Substituted Imidazopyridine Derivatives As Melanocortin-4 Receptor Antagonists

ABSTRACT

The present invention relates to substituted imidazopyridine derivatives as melanocortin-4 receptor (MC-4R) modulators, in particular as melanocortin-4 receptor antagonists. The antagonists are useful for the treatment of disorders and diseases such as cancer cachexia, muscle wasting, anorexia, amytrophic lateral sclerosis (ALS), anxiety and depression.

FIELD OF THE INVENTION

The present invention relates to substituted imidazopyridine derivativesas melanocortin-4 receptor modulators. Depending on the structure andthe stereochemistry, melanocortin-4 receptor modulators are eitheragonists or antagonists. The compounds of the invention are selectiveantagonists of the human melanocortin-4 receptor (MC-4R). Theantagonists are useful for the treatment of disorders and diseases suchas cancer cachexia, muscle wasting, anorexia, amytrophic lateralsclerosis (ALS), anxiety and depression.

BACKGROUND OF THE INVENTION

Melanocortins (MCs) stem from pro-opiomelanocortin (POMC) viaproteolytic cleavage. These peptides, adrenocorticotropic hormone(ACTH), α-melanocyte-stimulating hormone (α-MSH), α-MSH and γ-MSH, rangein size from 12 to 39 amino acids. The most important endogenous agonistfor central MC-4R activation appears to be the tridecapeptide α-MSH.Among MCs, it was reported that α-MSH acts as a neurotransmitter orneuromodulator in the brain. MC peptides, particularly α-MSH, have awide range of effects on biological functions including feedingbehavior, pigmentation and exocrine function. The biological effects ofα-MSH are mediated by a sub-family of 7-transmembrane G-protein-coupledreceptors, termed melanocortin receptors (MC-Rs). Activation of any ofthese MC-Rs results in stimulation of cAMP formation.

To date, five distinct types of receptor subtype for MC (MC-1R to MC-5R)have been identified and these are expressed in different tissues.

MC-1R was first found in melanocytes. Naturally occurring inactivevariants of MC-1R in animals were shown to lead to alterations inpigmentation and a subsequent lighter coat color by controlling theconversion of phaeomelanin to eumelanin through the control oftyrosinase. From these and other studies, it is evident that MC-1R is animportant regulator of melanin production and coat color in animals andskin color in humans. The MC-2R is expressed in the adrenal glandrepresenting the ACTH receptor. The MC-2R is not a receptor for α-MSHbut is the receptor for the adrenocorticotropic hormone I (ACTH I).

The MC-3R is expressed in the brain (predominately located in thehypothalamus) and peripheral tissues like gut and placenta, andknock-out studies have revealed that the MC-3R may be responsible foralterations in feeding behavior, body weight and thermogenesis.

The MC-4R is primarily expressed in the brain. Overwhelming data supportthe role of MC-4R in energy homeostasis. Genetic knock-outs andpharmacologic manipulation of MC-4R in animals have shown that agonizingthe MC-4R causes weight loss and antagonizing the MC-4R produces weightgain (A. Kask, et al., “Selective antagonist for the melanocortin-4receptor (HS014) increases food intake in free-feeding rats,” Biochem.Biophys. Res. Commun., 245: 90-93 (1998)).

MC-5R is ubiquitously expressed in many peripheral tissues includingwhite fat, placenta and a low level of expression is also observed inthe brain. However its expression is greatest in exocrine glands.Genetic knock-out of this receptor in mice results in altered regulationof exocrine gland function, leading to changes in water repulsion andthermoregulation. MC-5R knockout mice also reveal reduced sebaceousgland lipid production (Chen et al., Cell, 91: 789-798 (1997)).

Attention has been focused on the study of MC-3R and MC-4R modulatorsand their use in treating body weight disorders, such as obesity andanorexia. However, evidence has shown that the MC peptides have potentphysiological effects besides their role in regulating pigmentation,feeding behavior and exocrine function. In particular, α-MSH recentlyhas been shown to induce a potent anti-inflammatory effect in both acuteand chronic models of inflammation including inflammatory bowel-disease,renal ischemia/reperfusion injury and endotoxin-induced hepatitis.Administration of α-MSH in these models results in substantial reductionof inflammation-mediated tissue damage, a significant decrease inleukocyte infiltration and a dramatic reduction in elevated levels ofcytokines and other mediators to near baseline levels. Recent studieshave demonstrated that the anti-inflammatory actions of α-MSH aremediated by MC-1R. The mechanism by which agonism of MC-1R results in ananti-inflammatory response is likely through inhibition of thepro-inflammatory transcription activator, NF-κB. NF-κB is a pivotalcomponent of the pro-inflammatory cascade, and its activation is acentral event in initiating many inflammatory diseases. Additionally,anti-inflammatory actions of α-MSH may be, in part, mediated by agonismof MC-3R and/or MC-5R.

A specific single MC-R that may be targeted for the control of obesityhas not yet been identified, although evidence has been presented thatMC-4R signaling is important in mediating feeding behavior (S. Q.Giraudo et al., “Feeding effects of hypothalamic injection ofmelanocortin-4 receptor ligands,” Brain Research, 80: 302-306 (1998)).Further evidence for the involvement of MC-Rs in obesity includes: 1)the agouti (A^(vy)) mouse which ectopically expresses an antagonist ofthe MC-1R, MC-3R and MC-4R is obese, indicating that blocking the actionof these three MC-R's can lead to hyperphagia and metabolic disorders;2) MC-4R knockout mice (D. Huszar et al., Cell, 88: 131-141 (1997))recapitulate the phenotype of the agouti mouse and these mice are obese;3) the cyclic heptapeptide melanotanin II (MT-II) (a non-selectiveMC-1R, -3R, -4R, and -5R agonist) injected intracerebroventricularly(ICV) in rodents, reduces food intake in several animal feeding models(NPY, ob/ob, agouti, fasted) while ICV injected SHU-9119 (MC-3R and 4Rantagonist; MC-1R and -5R agonist) reverses this effect and can inducehyperphagia; 4) chronic intraperitoneal treatment of Zucker fatty ratswith an α-NDP-MSH derivative (HP-228) has been reported to activateMC-1R, -3R, -4R, and -5R and to attenuate food intake and body weightgain over a 12 week period (I. Corcos et al., “HP-228 is a potentagonist of melanocortin receptor-4 and significantly attenuates obesityand diabetes in Zucker fatty rats,” Society for Neuroscience Abstracts,23: 673 (1997)).

MC-4R appears to play a role in other physiological functions as well,namely controlling grooming behavior, erection and blood pressure.Erectile dysfunction denotes the medical condition of inability toachieve penile erection sufficient for successful intercourse. The term“impotence” is often employed to describe this prevalent condition.Synthetic melanocortin receptor agonists have been found to initiateerections in men with psychogenic erectile dysfunction (H. Wessells etal., “Synthetic Melanotropic Peptide Initiates Erections in Men WithPsychogenic Erectile Dysfunction: Double-Blind, Placebo ControlledCrossover Study,” J. Urol., 160: 389-393, 1998). Activation ofmelanocortin receptors of the brain appears to cause normal stimulationof sexual arousal. Evidence for the involvement of MC-R in male and/orfemale sexual dysfunction is detailed in WO 00/74679.

Diabetes is a disease in which a mammal's ability to regulate glucoselevels in the blood is impaired because the mammal has a reduced abilityto convert glucose to glycogen for storage in muscle and liver cells. InType I diabetes, this reduced ability to store glucose is caused byreduced insulin production. “Type II diabetes” or “Non-Insulin DependentDiabetes Mellitus” (NIDDM) is the form of diabetes which is due to aprofound resistance to insulin stimulating or regulatory effect onglucose and lipid metabolism in the main insulin-sensitive tissues,muscle, liver and adipose tissue. This resistance to insulinresponsiveness results in insufficient insulin activation of glucoseuptake, oxidation and storage in muscle, and inadequate insulinrepression of lipolysis in adipose tissue and of glucose production andsecretion in liver. When these cells become desensitized to insulin, thebody tries to compensate by producing abnormally high levels of insulinand hyperinsulemia results. Hyperinsulemia is associated withhypertension and elevated body weight. Since insulin is involved inpromoting the cellular uptake of glucose, amino acids and triglyceridesfrom the blood by insulin sensitive cells, insulin insensitivity canresult in elevated levels of triglycerides and LDL which are riskfactors in cardiovascular diseases. The constellation of symptoms whichincludes hyperinsulemia combined with hypertension, elevated bodyweight, elevated triglycerides and elevated LDL, is known as Syndrome X.MC-4R agonists might be useful in the treatment of NIDDM and Syndrome X.

Among MC receptor subtypes, the MC4 receptor is also of interest interms of the relationship to stress and the regulation of emotionalbehavior, as based on the following findings. Stress initiates a complexcascade of responses that include endocrine, biochemical and behavioralevents. Many of these responses are initiated by release ofcorticotropin-releasing factor (CRF) (Owen M J and Nemeroff C B (1991)Physiology and pharmacology of corticotrophin releasing factor.Pharmacol Rev 43: 425-473). In addition to activation of the brain CRFsystem, there are several lines of evidence that melanocortins (MCs),which stem from proopiomelanocortin by enzymatic processing, mediateimportant behavioral and biochemical responses to stress and,consequently, stress-induced disorders like anxiety and depression(Anxiolytic-Like and Antidepressant-Like Activities of MCL0129(1-[(S)-2-(4-Fluorophenyl)-2-(4-isopropylpiperadin-1-yl)ethyl]-4-[4-(2-methoxynaphthalen-1-yl)butyl]piperazine),a Novel and Potent Nonpeptide Antagonist of the Melanocortin-4 Receptor;Shigeyuki Chaki et al, J. Pharm. Exp. Ther. (2003) 304(2), 818-26).

Chronic diseases, such as malignant tumors or infections, are frequentlyassociated with cachexia resulting from a combination of a decrease inappetite and a loss of lean body mass. Extensive loss of lean body massis often triggered by an inflammatory process and is usually associatedwith increased plasma levels of cytokines (e.g. TNF-α), which increasethe production of α-MSH in the brain. Activation of MC4 receptors in thehypothalamus by α-MSH reduces appetite and increases energy expenditure.Experimental evidence in tumor bearing mice suggests that cachexia canbe prevented or reversed by genetic MC4 receptor knockout or MC4receptor blockade. The increased body weight in the treated mice isattributable to a larger amount of lean body mass, which mainly consistsof skeletal muscle (Marks D. L. et al. Role of the central melanocortinsystem in cachexia. Cancer Res. (2001) 61: 1432-1438).

Clinical observations indicate, that progression of amytrophic lateralsclerosis (ALS) might be inversely correlated with body weight (e.g.Ludolph A C, Neuromuscul Disord. (2006) 16 (8):530-8). Accordingly,MC-4R inhibitors could be used to treat ALS patients.

Melanocortin-4-receptor modulators have been previously described in theliterature. For example, substituted phenylpiperidine derivatives havebeen synthesized and explored as MC-4R agonists as well as antagonists.

In view of the unresolved deficiencies in treatment of various diseasesand disorders as discussed above, it is an object of the presentinvention to provide novel compounds with improved ability to cross theblood brain barrier, which are useful as melanocortin-4 receptorantagonists to treat cancer cachexia, muscle wasting, anorexia,amytrophic lateral sclerosis (ALS), anxiety, depression and otherdiseases with MC-4R involvement.

Surprisingly, it has been found that novel imidazopyridines according toformula (I) shown below solve the object of the present invention.

SUMMARY OF THE INVENTION

The present invention relates to substituted imidazopyridine derivativesof structural formula (I)

wherein R¹, R², R³, A and X are defined as described below.

The imidazopyridine derivatives of structural formula (I) are effectiveas melanocortin receptor modulators and are particularly effective asselective melanocortin-4 receptor (MC-4R) antagonists. They aretherefore useful for the treatment of disorders where the inactivationof the MC-4R is involved. The antagonists are useful for the treatmentof disorders and diseases such as cancer cachexia, muscle wasting,anorexia, amytrophic lateral sclerosis, anxiety and depression.

Thus, the present inventions relates to compounds of formula (I) for thetreatment and/or prophylaxis of cancer cachexia, muscle wasting,anorexia, amytrophic lateral sclerosis (ALS), anxiety and depression.

In a further aspect, the invention relates to the use of a compound offormula (I) for the preparation of a medicament for the treatment and/orprophylaxis of cancer cachexia, muscle wasting, anorexia, amytrophiclateral sclerosis (ALS), anxiety and depression.

The present invention also relates to pharmaceutical compositionscomprising the compounds of the present invention and a pharmaceuticallyacceptable carrier.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to substituted imidazopyridine derivativesuseful as melanocortin receptor modulators, in particular, selectiveMC-4R antagonists.

SubstitutedN-benzyl-N-methyl-2-phenyl-5-diethylamido-3-methylamino-imidazo[1,2-a]pyridinesare known from WO-A-02/066478 which describes antagonists ofgonadotropin releasing hormone. The present invention relates to novelimidazopyridines which are used as antagonists of MC-4R.

The compounds of the present invention are represented by structuralformula (I)

and enantiomers, diastereomers, tautomers, solvates and pharmaceuticallyacceptable salts thereof,wherein

-   A is —NH—, —CH₂—, —CH₂—CH₂— or a bond;-   X is H,    -   phenyl,    -   phenyl which is fused with a saturated heterocyclic 5- or        6-membered ring, wherein the heterocyclic ring may contain 1 or        2 heteroatoms selected from O and N and wherein the heterocyclic        ring may further be optionally substituted by an oxo group,    -   4 to 8-membered saturated or unsaturated heterocyclyl containing        1 or 2 heteroatoms selected from N, O and S,    -   5- to 6-membered heteroaryl containing 1 or 2 heteroatoms        selected from N, O and S, or    -   —C(O)—R⁶,    -   wherein each phenyl, heterocyclyl and heteroaryl is optionally        substituted by 1 to 3 R¹⁴ and/or 1R^(4b) and/or 1R⁵;-   R¹ and R² are independently from each other selected from    -   H,    -   C₁₋₆ alkyl,    -   C₁₋₆ alkylene-O—C₁₋₆ alkyl,    -   C₁₋₃ alkylene-heterocyclyl,    -   C₁₋₆ alkylene-C₃₋₇ cycloalkyl,    -   wherein each alkyl, alkylene, heterocyclyl and cycloalkyl is        optionally substituted by OH, or    -   R¹ and R² form together with the nitrogen atom to which they are        attached a 5- to 6-membered ring which may additionally contain        1 oxygen atom in the ring and which is optionally substituted by        one or more substituents selected from OH, C₁₋₆ alkyl, O—C₁₋₆        alkyl, C₀₋₃ alkylene-C₃₋₅ cycloalkyl, C₁₋₆ alkylene-O—C₁₋₆ alkyl        or (CH₂)₀₋₃-phenyl;-   R^(4a) is halogen,    -   CN,    -   C₁₋₆ alkyl, optionally substituted with one or more halogen        atoms, O—C₁₋₆ alkyl, optionally substituted with one or halogen        atoms, or OH;-   R^(4b) is C(O)NH₂,    -   C(O)OH,    -   C(O)NH—C₁₋₆ alkyl,    -   C(O)N—(C₁₋₆ alkyl)₂,    -   SO₂—C₁₋₆ alkyl,    -   C(O)NH—SO₂—C₁₋₆ alkyl,    -   oxo, whereby the ring is at least partially saturated,    -   NH₂,    -   NH—C₁₋₆ alkyl,    -   N—(C₁₋₆ alkyl)₂,    -   NH—SO₂—CH₃, or    -   NH—SO₂—CF₃;-   R⁵ is 5 to 6-membered saturated or unsaturated heterocyclyl    containing 1 to 3 heteroatoms selected from N, O and S or    -   5 to 6-membered heteroaryl containing 1 to 3 heteroatoms        selected from N, O and S,    -   wherein the heterocyclyl and the heteroaryl are optionally        substituted by 1 or 2 R¹⁴;-   R⁶ is H,    -   C₁₋₆ alkyl, optionally substituted with one or more halogen        atoms, phenyl or    -   4 to 8-membered saturated or unsaturated heterocyclyl containing        1 to 3 heteroatoms selected from N, O and S,    -   wherein each phenyl or heterocyclyl is optionally substituted by        1 to 3 R¹⁴ and/or 1R⁸;-   R³ is —(CR⁸R⁹)_(n)-T;-   R⁸ and R⁹ are independently from each other selected from    -   H,    -   OH,    -   halogen,    -   C₁₋₆ alkyl, and    -   O—C₁₋₆ alkyl;-   n is 1, 2, 3, 4, 5 or 6;-   T is

-   -   or NR¹²R¹³;

-   R¹⁰ is H,    -   NH₂,    -   OH,    -   C₁₋₆ alkyl, optionally substituted by one or more substituents        selected from halogen, OH and O—C₁₋₆ alkyl,    -   O—C₁₋₆ alkyl, wherein alkyl is optionally substituted by one or        more substituents selected from halogen, OH and O—C₁₋₆ alkyl,    -   halogen,    -   NH(C₁₋₆ alkyl),    -   N(C₁₋₆ alkyl)₂,    -   phenyl or    -   heteroaryl,    -   wherein phenyl and heteroaryl are optionally substituted by 1 to        3 R^(4a);

-   q is 1 or 2;

-   Y is CH₂, NR¹¹ or O;

-   R¹¹ is H,    -   C₁₋₆ alkyl, or    -   (CH₂)₀₋₆—C₃₋₇ cycloalkyl;

-   R¹² and R¹³ are independently from each other selected from    -   H,    -   C₁₋₆ alkyl,    -   C₂₋₆ alkenyl,    -   C₂₋₆ alkinyl,    -   (CH₂)₀₋₂—C₃₋₇ cycloalkyl and    -   C₁₋₆ alkylene-O—C₁₋₆ alkyl,    -   wherein C₁₋₆ alkyl, C₁₋₆ alkylene and C₃₋₇ cycloalkyl are        optionally substituted by 1 to 3 R¹⁴;

-   R¹⁴ is halogen,    -   CN,    -   C₁₋₆ alkyl, optionally substituted with one or more substituents        selected from halogen, OH, O—C₁₋₆ alkyl, O—C₃₋₇ cycloalkyl,        O—C(O)C₁₋₆ alkyl, O—C(O)C₃₋₇ cycloalkyl,    -   O—C₁₋₆ alkyl, optionally substituted with one or more        substituents selected from halogen, OH, O—C₁₋₆ alkyl, O—C₃₋₇        cycloalkyl, O—C(O)C₁₋₆ alkyl, O—C(O)C₃₋₇ cycloalkyl, or    -   OH.

In a preferred embodiment, the variant A represents NH— or a bond. Morepreferably, A represents a bond.

It is further preferred that R¹ and R² independently from each otherrepresent C₃₋₆alkyl or that R¹ and R² form together with the nitrogenatom to which they are attached a 5 to 6-membered ring which mayadditionally contain one oxygen atom in the ring and which is optionallysubstituted by one or more substituents selected from OH, C₁₋₆ alkyl,C₀₋₃ alkylene-C₃₋₅ cycloalkyl, O—C₁₋₆ alkyl, C₁₋₆alkylene-O—C₁₋₆ alkylor (CH₂)₀₋₃-phenyl. More preferably, R¹ and R² independently from eachother represent C₃₋₆ alkyl.

In a preferred embodiment, the variant T is NR¹²R¹³. Therein, thevariants R¹² and R¹³ are preferably independently from each otherselected from H, C₁₋₃ alkyl or (CH₂)₀₋₂—C₃₋₆ cycloalkyl, wherein alkyland cycloalkyl are optionally substituted by 1 to 3 R¹⁴.

In an alternative preferred embodiment, the variant T is selected from

It is preferred that the variant Y is CH₂ or NR¹¹. Preferably, R¹¹ ishydrogen.

It is further preferred that R¹⁰ is selected from H, NH₂, C₁₋₆ alkyl,NH(C₁₋₆ alkyl) or N(C₁₋₆alkyl)₂. More preferably, R¹⁰ is H, NH₂ or C₁₋₆alkyl.

Regarding the variant X, said variant preferably represents H, phenylwhich is fused with a saturated heterocyclic 6-membered ring, whereinthe heterocyclic ring may contain 1 or 2 heteroatoms selected from O andN and wherein the heterocyclic ring may further be optionallysubstituted by an oxo group, or X represents a 4 to 8-membered saturatedor unsaturated heterocyclyl containing 1 or 2 heteroatoms selected fromN, O and S, wherein each phenyl and heterocyclyl is optionallysubstituted by 1 to 3 R¹⁴ and/or 1R^(4b) and/or 1 R⁵.

In an equally preferred embodiment, the variant X represents phenyl or a5 to 6-membered heteroaryl containing 1 or 2 heteroatoms selected fromN, O and S, wherein each phenyl and heteroaryl is optionally substitutedby 1 to 3 R¹⁴ and/or 1R^(4b) and/or R⁵. More preferably, X is phenyl orpyridyl, most preferably X is phenyl.

Compounds of the formula (I) in which some or all of the above-mentionedgroups have the preferred or more preferred meanings are also an objectof the present invention.

In the above and the following, the employed terms have the meaning asdescribed below:

Alkyl is a straight chain or branched alkyl having 1, 2, 3, 4, 5 or 6carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, or hexyl.

Alkenyl is a straight chain or branched alkyl having 2, 3, 4, 5 or 6carbon atoms and one to three double bonds, preferably one or two doublebonds, most preferably one double bound. Preferred examples of a C₂₋₆alkenyl group are ethenyl, prop-1-enyl, prop-2-enyl, isoprop-1-enyl,n-but-1-enyl, n-but-2-enyl, n-but-3-enyl, isobut-1-enyl, isobut-2-enyl,n-pent-1-enyl, n-pent-2-enyl, n-pent-3-enyl, n-pent-4-enyl,n-pent-1,3-enyl, isopent-1-enyl, isopent-2-enyl, neopent-1-enyl,n-hex-1-enyl, n-hex-2-enyl, n-hex-3-enyl, n-hex-4-enyl, n-hex-5-enyl,n-hex-1,3-enyl, n-hex-2,4-enyl, n-hex-3,5-enyl, and n-hex-1,3,5-enyl.More preferred examples of a C₂₋₆ alkenyl group are ethenyl andprop-1-enyl.

Alkinyl is a straight chain or branched alkyl having 2, 3, 4, 5 or 6carbon atoms and one to three triple bonds, preferably one or two triplebonds, most preferably one triple bond. Preferred examples of a C₂₋₆alkinyl group are ethinyl, prop-1-inyl, prop-2-inyl, n-but-1-inyl,n-but-2-inyl, n-but-3-inyl, n-pent-1-inyl, n-pent-2-inyl, n-pent-3-inyl,n-pent-4-inyl, n-pent-1,3-inyl, isopent-1-inyl, neopent-1-inyl,n-hex-1-inyl, n-hex-2-inyl, n-hex-3-inyl, n-hex-4-inyl, n-hex-5-inyl,n-hex-1,3-inyl, n-hex-2,4-inyl, n-hex-3,5-inyl and n-hex-1,3,5-inyl.More preferred examples of a C₂₋₆ alkinyl group are ethinyl andprop-1-inyl.

Cycloalkyl is an alkyl ring having preferably 3, 4, 5, 6 or 7 carbonatoms at the most, such as cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl or cycloheptyl, more preferably 3, 4, 5 or 6 carbon atoms.

Heteroaryl is an aromatic moiety having 1, 2, 3, 4 or 5 carbon atoms andat least one heteratom selected from O, N and/or S and is preferablyselected from thienyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl,pyrazinyl, pyrimidinyl, pyridazinyl, isothiazolyl, isoxazyl, furanyl,and indazolyl, more preferably from thienyl, furanyl, imidazlyl,pyridyl, and pyrimidinyl.

Heterocyclyl is a saturated or unsaturated ring containing at least oneheteroatom selected from O, N and/or 5 and 1, 2, 3, 4, 5, 6 or 7 carbonatoms. Preferably, hetero-cyclyl is a 4 to 8-membered ring and ispreferably selected from tetrahydrofuranyl, azetidinyl, pyrrolidinyl,piperidinyl, pyranyl, morpholinyl, thiomorpholinyl, more preferably frompiperidinyl and pyrrolidinyl.

Halogen is a halogen atom selected from F, Cl, Br and I, preferably fromF, Cl and Br.

The compounds of structural formula (I) are effective as melanocortinreceptor modulators and are particularly effective as selectivemodulators of MC-4R. They are useful for the treatment and/or preventionof disorders responsive to the inactivation of MC-4R, such as cancercachexia, muscle wasting, anorexia, amytrophic lateral sclerosis,anxiety, depression and other diseases with MC-4R involvement.

Optical Isomers—Diastereomers—Geometric Isomers—Tautomers

Compounds of structural formula (I) contain one or more asymmetriccenters and can occur as racemates and racemic mixtures, singleenantiomers, diastereomeric mixtures and individual diastereomers. Thepresent invention is meant to comprehend all such isomeric forms of thecompounds of structural formula (I).

Compounds of structural formula (I) may be separated into theirindividual diastereoisomers by, for example, fractional crystallizationfrom a suitable solvent, for example methanol or ethyl acetate or amixture thereof, or via chiral chromatography using an optically activestationary phase. Absolute stereochemistry may be determined by X-raycrystallography of crystalline products or crystalline intermediateswhich are derivatized, if necessary, with a reagent containing anasymmetric center of known absolute configuration.

Alternatively, any stereoisomer of a compound of the general formula (I)may be obtained by stereospecific synthesis using optically purestarting materials or reagents of known absolute configuration.

Salts

The term “pharmaceutically acceptable salts” refers to salts preparedfrom pharmaceutically acceptable non-toxic bases or acids includinginorganic or organic bases and inorganic or organic acids. Salts derivedfrom inorganic bases include aluminum, ammonium, calcium, copper,ferric, ferrous, lithium, magnesium, manganic salts, manganous,potassium, sodium, zinc and the like. Particularly preferred are theammonium, calcium, lithium, magnesium, potassium and sodium salts. Saltsderived from pharmaceutically acceptable organic non-toxic bases includesalts of primary, secondary and tertiary amines, substituted aminesincluding naturally occurring substituted amines, cyclic amines andbasic ion exchange resins, such as arginine, betaine, caffeine, choline,N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,2-dimethylamino-ethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lysine, methylglucamine, morpholine,piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine, tromethamineand the like.

When the compound of the present invention is basic, salts may beprepared from pharmaceutically acceptable non-toxic acids, includinginorganic and organic acids. Such acids include acetic, benzenesulfonic,benzoic, camphorsulfonic, citric, ethanesulfonic, formic, furnaric,gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic,maleic, malic, mandelic, methanesulfonic, malonic, mucic, nitric,parnoic, pantothenic, phosphoric, propionic, succinic, sulfuric,tartaric, p-toluenesulfonic, trifluoroacetic acid and the like.Particularly preferred are citric, fumaric, hydrobromic, hydrochloric,maleic, phosphoric, sulfuric and tartaric acids.

It will be understood that, as used herein, references to the compoundsof formula (I) are meant to also include the pharmaceutically acceptablesalts.

Utility

Compounds of formula (I) are melanocortin receptor antagonists and assuch are useful in the treatment, control or prevention of diseases,disorders or conditions responsive to the inactivation of one or more ofthe melanocortin receptors including, but not limited to, MC-1R, MC-2R,MC-3R, MC-4R or MC-5R. Such diseases, disorders or conditions include,but are not limited to, cancer cachexia, muscle wasting, anorexia,amytrophic lateral sclerosis, anxiety and depression.

The compounds of formula (I) can be further used in the treatment,control or prevention of diseases, disorders or conditions which areresponsive to the inactivation of one or more melanocortin receptorsincluding, but not limited to, MC-1R, MC-2R, MC-3R, MC-4R or MC-5R. Suchdiseases, disorders or conditions include, but are not limited to,hypertension, hyperlipidemia, osteoarthritis, cancer, gall bladderdisease, sleep apnea, compulsion, neuroses, insomnia/sleep disorder,substance abuse, pain, fever, inflammation, immune-modulation,rheumatoid arthritis, skin tanning, acne and other skin disorders,neuroprotective and cognitive and memory enhancement including thetreatment of Alzheimer's disease.

Administration and Dose Ranges

Any suitable route of administration may be employed for providing amammal, especially a human with an effective dosage of a compound of thepresent invention. For example, oral, rectal, topical, parenteral,ocular, pulmonary, nasal and the like may be employed. Dosage formsinclude tablets, troches, dispersions, suspensions, solutions, capsules,creams, ointments, aerosols and the like. Preferably compounds offormula (I) are administered orally or topically.

The effective dosage of active ingredient employed may vary depending onthe particular compound employed, the mode of administration, thecondition being treated and the severity of the condition being treated.Such dosage may be ascertained readily by a person skilled in the art.

When treating cancer cachexia, muscle wasting or anorexia generallysatisfactory results are obtained when the compounds of the presentinvention are administered at a daily dosage of from about 0.001milligram to about 100 milligrams per kilogram of body weight,preferably given in a single dose or in divided doses two to six times aday, or in sustained release form. In the case of a 70 kg adult human,the total daily dose will generally be from about 0.07 milligrams toabout 3500 milligrams. This dosage regimen may be adjusted to providethe optimal therapeutic response.

Formulation

The compounds of formula (I) are preferably formulated into a dosageform prior to administration. Accordingly the present invention alsoincludes a pharmaceutical composition comprising a compound of formula(I) and a suitable pharmaceutical carrier.

The present pharmaceutical compositions are prepared by known proceduresusing well-known and readily available ingredients. In making theformulations of the present invention, the active ingredient (a compoundof formula (I)) is usually mixed with a carrier, or diluted by acarrier, or enclosed within a carrier, which may be in the form of acapsule, sachet, paper or other container. When the carrier serves as adiluent, it may be a solid, semisolid or liquid material which acts as avehicle, excipient or medium for the active ingredient. Thus, thecompositions can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,aerosol (as a solid or in a liquid medium), soft and hard gelatincapsules, suppositories, sterile injectable solutions and sterilepackaged powders.

Some examples of suitable carriers, excipients and diluents includelactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia,calcium phosphate, alginates, tragacanth, gelatin, calcium silicate,microcrystalline cellulose, polyvinylpyrrolidone, cellulose, watersyrup, methyl cellulose, methyl and propylhydroxybenzoates, talc,magnesium stearate and mineral oil. The formulations can additionallyinclude lubricating agents, wetting agents, emulsifying and suspendingagents, preserving agents, sweetening agents or flavoring agents. Thecompositions of the invention may be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient.

PREPARATION OF COMPOUNDS OF THE INVENTION

The compounds of formula (I) when existing as a diastereomeric mixture,may be separated into diastereomeric pairs of enantiomers by fractionalcrystallization from a suitable solvent such as methanol, ethyl acetateor a mixture thereof. The pair of enantiomers thus obtained may beseparated into individual stereoisomers by conventional means by usingan optically active acid as a resolving agent. Alternatively, anyenantiomer of a compound of the formula (I) may be obtained bystereospecific synthesis using optically pure starting materials orreagents of known configuration.

The compounds of formula (I) of the present invention can be preparedaccording to the procedures of the following Schemes and Examples, usingappropriate materials and are further exemplified by the followingspecific examples. Moreover, by utilizing the procedures describedherein, in conjunction with ordinary skills in the art, additionalcompounds of the present invention claimed herein can be readilyprepared. The compounds illustrated in the examples are not, however, tobe construed as forming the only genus that is considered as theinvention. The Examples further illustrate details for the preparationof the compounds of the present invention. Those skilled in the art willreadily understand that known variations of the conditions and processesof the following preparative procedures can be used to prepare thesecompounds. The instant compounds are generally isolated in the form oftheir pharmaceutically acceptable salts, such as those describedpreviously. The free amine bases corresponding to the isolated salts canbe generated by neutralization with a suitable base, such as aqueoussodium hydrogencarbonate, sodium carbonate, sodium hydroxide andpotassium hydroxide, and extraction of the liberated amine free baseinto an organic solvent followed by evaporation. The amine free baseisolated in this manner can be further converted into anotherpharmaceutically acceptable salt by dissolution in an organic solventfollowed by addition of the appropriate acid and subsequent evaporation,precipitation or crystallization. All temperatures are degrees Celsius.

In the schemes, preparations and examples below, various reagent symbolsand abbreviations have the following meanings

AcOH acetic acidAc₂O acetic anhydrideBoc tert-butoxycarbonylbp boiling pointCDI 1,1′-carbonyldiimidazoleDCE 1,2-dichloroethaneDCM dichloromethaneDIEA ethyl-diisopropylamine

DMF N,N-dimethylformamide

DMSO dimethylsulfoxideEDC 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochlorideEt₂O diethyl etherEtOAc ethyl acetateHATU O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphateHOAt 1-hydroxy-7-azabenzotriazoleHOBt 1-hydroxybenzotriazoleh hour(s)MeCN acetonitrileMeLi methyllithiumMeOH methanolMs mesyl

NMM N-methylmorpholine

MW molecular weightPG protecting groupRT room temperatureTEA triethylamineTFAA trifluoroacetic acid anhydrideTHF tetrahydrofuraneTMSI trimethylsilyl iodidet_(R) (min) HPLC retention timeTs tosylZ benzyloxycarbonyl

As shown in Reaction Scheme 1, optionally substituted amine and2-amino-pyridine-5-carboxylic acid are reacted in an amide couplingreaction in the presence of a coupling reagent such as EDC in an organicsolvent such as DMF or DCM at a suitable temperature. The resultingamide can then be reacted with a sulfonylchloride in a solvent such aspyridine or any other appropriate solvent and an organic base such astriethylamine to yield the corresponding sulfonylamino-amides.

Alternatively, 2-amino-pyridine-5-carboxylic acid methyl ester can bereacted under the conditions described above to yield the correspondingsulfonylamino-esters, as shown in Reaction Scheme 2.

As shown in Reaction Scheme 3, optionally substitutedω-alkoxycarbonyl-α-bromoketones can be obtained from the correspondingketone by reacting it for example with copper(II) bromide in a solventsuch as mixture of ethyl acetate and chloroform at an appropriatetemperature for a given time. The resulting α-bromoketones can then bereacted with sulfonylamino-amides in a solvent such as MeCN in thepresence of an appropriate base, for example DIEA, to yield theN-alkylated sulfonylamino-amides. These intermediates can then befurther cyclised to the corresponding imidazo[1,2-a]pyridines bytreating them with TFAA in a suitable solvent such as DCM or1,2-dichloroethane at an appropriate temperature for a given time. Esterfunction of optionally substituted imidazo[1,2-a]pyridines can behydrolyzed under basic conditions using a reagent like lithium hydroxidemonohydrate in a suitable solvent such as a mixture of water, THF andMeOH.

The resulting acid can be activated with a reagent such as isobutylchloroformate or CDI in the presence of a suitable base such asN-methylmorpholine in an appropriate solvent such as THF andsubsequently be reduced to the corresponding alcohol with a reducingagent such as sodium borohydride in an appropriate solvent such as amixture of THF and water. The alcohol function can be converted to aleaving group with a reagent such as mesyl chloride or tosyl chloride inan appropriate solvent such as mixture of DCM and THF in the presence ofa suitable base like TEA. Product of this reaction can be treated withan amine T-H in an appropriate solvent like MeCN to yield the targetmolecule.

As shown in Reaction Scheme 4, methyl ester functions of optionallysubstituted imidazo[1,2-a]pyridines can be reduced to the correspondingalcohol with a reagent such as sodium borohydride in an appropriatesolvent like methanol. The alcohol can be further reacted to the targetmolecules as depicted in Reaction Scheme 3.

As shown in Reaction Scheme 5, optionally substituted α-bromoketonesbearing a acetal function in ω-position can be obtained from thecorresponding ketones and converted to the corresponding optionallysubstituted imidazo[1,2-a]pyridines as described above. The acetals canbe cleaved to form the corresponding aldehydes by using a reagent suchas 6N HCl in water. Optionally substituted aldehydes can be subjected toa reductive amination with an amine T-H in the presence of a reducingagent such as sodium triacetoxyborohydride in an appropriate solventlike DCE.

As shown in Reaction Scheme 6, optionally substituted N-protectedω-amino-α-bromoketones can be reacted with sulfonylamino-amides in asolvent such as MeCN in the presence of an appropriate base, for exampleDIEA, to yield the N-alkylated sulfonylamino-amides. These intermediatescan then be further cyclised to the correspondingimidazo[1,2-a]pyridines by treating them with TFAA in a suitable solventsuch as DCM or 1,2-dichloroethane at an appropriate temperature for agiven time. The side chain amine function can be deprotected using areagent such as TMSI in a suitable solvent such as MeCN in the case of aZ-protecting group. Phthalimids can be cleaved with hydrazine hydrate inan appropriate solvent like ethyl acetate. Optionally substitutedimidazo[1,2-a]pyridines, bearing the primary amino group in the sidechain can be directly tested in the biological assay or are subjected tofurther derivatization. For example, reaction with 1,5-dibromopentane inan appropriate solvent like 1,2-dichloroethane in the presence of asuitable base such as DIEA leads to the corresponding piperidinederivatives.

As shown in Reaction Scheme 7, optionally substituted lactones can beacylated with alkyl esters alkylOC(O)A-X in the presence of a suitablebase such as sodium hydride in an appropriate solvent like toluene atelevated temperature. Said acylated lactones can be converted toω-chloroketones by heating the lactones in concentrated hydrochloricacid. Reaction of optionally substituted ω-chloroketones with forexample copper (II) bromide in a solvent such as mixture of ethylacetate and chloroform at an appropriate temperature for a given timeleads to the corresponding ω-chloro-α-bromoketones. Theω-chloro-α-bromoketones can then be reacted with sulfonylamino-amides ina solvent such as MeCN in the presence of an appropriate base, forexample DIEA, to yield the N-alkylated sulfonylamino-amides. Theseintermediates can then be further cyclised to the correspondingimidazo[1,2-a]pyridines by treating them with TFAA in a suitable solventsuch as DCM or 1,2-dichloroethane at an appropriate temperature for agiven time. The capping group T can be inserted by reacting thechloroalkyl substituted imidazo[1,2-a]pyridines, with an capping groupT-H in an appropriate solvent such as MeCN. When T-H is used in form ofa hydrochloride, a suitable base such as DIEA is used in addition toliberate the free amine T-H.

As shown in Reaction Scheme 8, optionally substitutedω-chloro-α-bromoketones can also be reacted with a sulfonylamino-esterin a solvent such as MeCN in the presence of an appropriate base, forexample DIEA, to yield the N-alkylated sulfonylamino-esters. Theseintermediates can then be further cyclised to the correspondingimidazo[1,2-a]pyridines by treating them with TFAA in a suitable solventsuch as DCM or 1,2-dichloroethane at an appropriate temperature for agiven time. The capping group T can be inserted by reacting thechloroalkyl substituted imidazo[1,2-a]pyridines with a capping group T-Hin an appropriate solvent such as MeCN. When T-His used in form of ahydrochloride, a suitable base such as DIEA is used in addition toliberate the free amine T-H. Ester function of optionally substitutedimidazo[1,2-a]pyridines can be hydrolyzed under basic conditions using areagent like lithium hydroxide monohydrate in a suitable solvent such asa mixture of water, THF and MeOH. The product of the saponification canbe isolated as lithium salt or as the corresponding acid. Alternatively,the ester function can also be cleaved under acidic conditions forexample using a reagent such as aqueous hydrochloric acid. The productof the ester cleavage can be introduced into the next step as acid orlithium salt. Amide formation can be achieved using standard peptidecoupling procedures. The acid can be coupled with an amine HNR¹R² in thepresence of EDC/HOBt, EDC/HOAt, HATU, a base such asdiisopropylethylamine and a solvent such as dichloromethane. A suitablesolvent, such as DCM, DMF, THF or a mixture of the above solvents, canbe used for the coupling procedure. A suitable base includestriethylamine (TEA), diisopropylethylamine (DIEA), N-methylmorpholine(NMM), collidine or 2,6-lutidine. A base may not be needed when EDC/HOBtis used.

Optionally substituted imidazo[1,2-a]pyridines bearing a chloropyridineor bromopyridine as residue A-X can be converted to the correspondingpyridones using a reagent such as aqueous hydrochloric acid at asuitable temperature as shown in Reaction Scheme 9. At the same time theester function is also hydrolyzed. The acids can be coupled with aminesHNR¹R² as described above.

As shown in Reaction Scheme 10 optionally substituted bromoketones canbe obtained in a three step reaction sequence starting from carboxylicacids. Said carboxylic acids can be converted to the correspondingWeinreb amides using N,O-dimethylhydroxylamine hydrochloride with acoupling reagent like EDC in the presence of a suitable base like NMM inan appropriate solvent such as DCM. The Weinreb amides can be convertedto the corresponding methyl ketones using a reagent such asmethyllithium in an inert solvent like THF at a suitable temperature.Bromination can be achieved using a mixture of bromine and hydrogenbromide in acetic acid.

As shown in Reaction Scheme 11 optionally substitutedaminopyridine-amides, which can be obtained as shown in Reaction Scheme1, can be converted to imidazo[1,2-a]pyridine 6-carboxylic acid amidesby reaction with α-bromoketones in a solvent like MeCN. This reactioncan be carried out either in a flask in refluxing solvent or any otherappropriate temperature or in a microwave reaction system. The reactionproducts can be purified by standard procedures or may precipitatedirectly from the solution upon cooling and may thus be used insubsequent reactions without further purification.

As shown in Reaction Scheme 12, products from Reaction Scheme 11optionally substituted imidazo[1,2-a]pyridine acid amides may be used ina Mannich reaction to give 3-aminomethyl-imidazo[1,2-a]pyridine6-carboxylic acid amides by reacting the imidazo[1,2-a]pyridine6-carboxylic acid amides with an appropriate amine and aqueousformaldehyde solution in a solvent such as acetic acid. Diaminescontaining one nitrogen-protecting group can be further deprotected bytreating the compound with an acid such as for example HCl in dioxane orTFA in DCM. Such compounds can then be purified by standard purificationprocedures such as flash chromatography or preparative HPLC.

As depicted in Reaction Scheme 13, optionally substitutedimidazo[1,2-a]pyridine 6-carboxylic acid amides can be reacted in aMichael addition reaction with α,β-unsaturated aldehydes in a solventsuch as a mixture of acetic acid and acetic anhydride at elevatedtemperature. The reaction may also be carried out in a microwavereactor. The product of this reaction can be treated with a base such assodium bicarbonate in a suitable solvent like a mixture of water andmethanol to yield the corresponding aldehydes which can be subjected toa reductive amination with an amine T-H in the presence of a reducingagent such as sodium triacetoxyborohydride in an appropriate solventlike DCE. Alternatively, optionally substituted imidazo[1,2-a]pyridine6-carboxylic acid esters can be used as starting materials. In this casethe ester function can be converted to the amide after introduction ofthe side chain CH₂CHR⁸CH₂T using the methods described in ReactionScheme 8.

As shown in Reaction Scheme 14, Michael addition of optionallysubstituted imidazo[1,2-a]pyridine 6-carboxylic acid amides can also beperformed with α,β-unsaturated ketones using the reaction conditionsdescribed in Reaction Scheme 13. In this case the product of the Michaeladdition reaction can be directly subjected to the reductive aminationreaction.

The products from Reaction Scheme 3, optionally substitutedimidazo[1,2-a]pyridines bearing a carboxylate function in the side chaincan be activated with a reagent such as CDI in an appropriate solventlike DCM and subsequently being reacted with N,O-dimethyl hydroxylaminehydrochloride in the presence of a suitable base such as DIEA. Reactionof the product with a reagent such as methyllithium in a suitablesolvent such as THF or diethyl ether leads to the corresponding ketoneswhich can be reductively aminated with an amine T-H in the presence of areducing agent such as sodium triacetoxyborohydride in an appropriatesolvent like DCE.

Optionally substituted imidazo[1,2-a]pyridines bearing a2-chloropyridine substituent can be reacted with amines as shown inReaction Scheme 16. The chloropyridines can be reacted with neat aminesHR^(4b) at elevated temperature to yield the corresponding2-aminopyridines. The reaction may also be carried out in a microwavereactor. Benzyl protecting groups can be removed by treatingN-benzylated 2-aminopyridines with a reagent such astrifluoromethanesulfonic acid in an inert solvent like DCM at anappropriate temperature.

As shown in Reaction Scheme 17, optionally substitutedimidazo[1,2-a]pyridines bearing a 2-chloropyridine substituent can bereacted with an alcoholate to form the corresponding alkoxypyridines.The alcoholate can be prepared from the corresponding alcohol HR¹⁴ usinga suitable base such as sodium hydride in an appropriate solvent likeDMF. Reaction of the alcoholate with the chloropyridine can be achievedat elevated temperatures.

Optionally substituted imidazo[1,2-a]pyridines bearing a pyridone moietycan be N-alkylated as shown in Reaction Scheme 18. The pyridone nitrogencan be alkylated with an alkylbromide Br—R¹⁴ in the presence of a basesuch as cesium carbonate or potassium carbonate in a suitable solventlike acetone at an appropriate temperature. Alcohol substituents onresidue R¹⁴ can be protected for example as esters. After the alkylationreaction the free alcohol can be obtained by hydrolyzing the ester witha reagent such as lithium hydroxide monohydrate in an appropriatesolvent like a mixture of water and THF.

Analytical LC-MS

The compounds of the present invention according to formula (I) wereanalyzed by analytical LC-MS. The conditions are summarized below.

Analytical Conditions Summary:

LC10Advp-Pump (Shimadzu) with SPD-M10Avp (Shimadzu) UV/Vis diode arraydetector and QP2010 MS-detector (Shimadzu) in ESI+ modus withUV-detection at 214, 254 and 275 nm,

Column: Waters XTerra MS C18, 3.5 μm, 2.1*100 mm,

linear gradient with acetonitrile in water (0.15% HCOOH), exception:methods D and E (curve gradient)Flow rate of 0.4 ml/min;

Mobile Phase A: water (0.15% HCOOH) Mobile Phase B: acetonitrile (0.15%HCOOH)

Methods are: A:

linear gradient from 5% to 95% acetonitrile in water (0.1% HCOOH)

0.00 min  5% B 5.00 min 95% B 5.10 min 99% B 6.40 min 99% B 6.50 min  5%B 8.00 min Pump STOP

B:

linear gradient from 10% to 90% acetonitrile in water (0.1% HCOOH)

0.00 min 10% B 5.00 min 90% B 5.10 min 99% B 6.40 min 99% B 6.50 min  5%B 8.00 min Pump STOP

C:

linear gradient from 5% to 95% acetonitrile in water (0.1% HCOOH)

 0.00 min  5% B 10.00 min 95% B 10.10 min 99% B 11.40 min 99% B 11.50min  5% B 13.00 min Pump STOP

D:

start concentration 1% acetonitrile

9.00 B. Conc 30 10.00 B. Curve 3 12.00 B. Conc 99 15.00 B. Conc 99 15.20B. Conc 1 18.00 Pump STOP

E:

start concentration 10% acetonitrile

10.00 B. Conc 60 11.00 B. Curve 2 12.00 B. Conc 99 15.00 B. Conc 9915.20 B. Conc 10 18.00 Pump STOP

F:

start concentration 15% acetonitrile

12.00 B. Conc 99 15.00 B. Conc 99 15.20 B. Conc 15 18.00 STOP 0

The following describes the detailed examples of the invention which canbe prepared via the reaction schemes 1 to 18.

TABLE 1

MS MW HPLC (calc.) t_(R) free [M + H]⁺ No. salt A-X R³ (min) method base(found) 1 HCl

4.6 E 492.66 493 2 HCl

2.7 A 560.78 561 3 HCl

4.7 E 464.65 465 4 HCl

5.4 E 469.07 469 5 HCl

3.9 C 492.70 493 6 HCl

4.9 E 518.74 519 7 HCOOH

5.4 E 506.73 507 8 HCOOH

5.6 E 520.76 521 9 HCOOH

5.2 E 518.74 519 10 HCOOH

5.5 E 518.74 519 11 HCOOH

4.9 E 504.71 505 12 HCOOH

5.1 E 534.74 535 13 HCOOH

5.3 E 536.76 537 14 HCOOH

5.54 E 536.73 537 15 HCOOH

5.0 E 547.78 548 16 HCOOH

5.4 E 548.77 549 17 HCl

6.5 E 513.73 514 18 HCl

6.31 E 487.69 488 19 HCOOH

5.97 E 523.16 523 20 HCOOH

5.73 E 497.12 497 21 HCl

6.16 E 532.77 533 22 HCOOH

5.70 E 537.19 537 23 HCOOH

5.68 E 525.18 525 24 HCOOH

5.47 E 511.16 511 25 2 × HCOOH

5.54 E 531.74 532 26 2 × HCOOH

6.43 E 499.70 500 27 2 × HCOOH

5.69 E 528.74 529 28 2 × HCl

3.5 F 492.70 494 29 2 × HCl

3.6 F 506.73 507 30 2 × HCl

3.9 F 550.76 551 31 2 × HCl

3.8 F 532.77 534 32 2 × HCl

3.7 F 536.73 537 33 2 × HCl

2.7 A 534.74 535 34 2 × HCl

2.7 A 534.74 535 35 2 × HCOOH

5.77 E 566.81 567 36 3 × HCl

2.6 A 533.76 534 37 2 × HCl

2.7 A 520.71 521 38 2 × HCl

2.9 A 516.73 517 39 HCOOH

4.89 E 532.73 533 40 2 × HCOOH

6.24 E 503.73 504 41 2 × HCOOH

5.42 E 503.73 504 42 2 × HCOOH

6.45 E 524.15 525 43 2 × HCOOH

4.90 E 559.75 560 44 2 × HCOOH

4.99 E 505.70 506 45 2 × HCOOH

4.68 E 557.78 558 46 2 × HCOOH

5.04 E 479.67 480 47 HCl

5.7 E 479.67 480 48 2 × HCOOH

6.2 E 507.72 508 49 HCOOH

7.0 E 495.73 496 50 2 × HCOOH

5.67 E 532.73 533 51 2 × HCOOH

4.2 E 506.73 507 52 —

6.0 E 453.63 454 53 HCOOH

5.7 E 485.64 485 54 2 × HCOOH

5.60 E 532.77 533 55 HCOOH

6.0 E 489.70 490 56 HCOOH

4.6 E 489.70 490 57 HCOOH

6.2 E 503.73 504 58 HCOOH

5.9 E 477.69 478 59 —

4.9 E 505.70 506 60 2 × HCl

3.0 A 548.81 549 61 2 × HCOOH

5.6 E 469.69 470 62 2 × HCOOH

5.2 E 505.70 506 63 —

4.82 E 559.79 560 64 —

4.79 E 545.77 546 65 —

4.46 E 504.72 505 66 HCOOH

6.2 E 498.11 498 67 —

3.2 A 524.15 524 68 2 × HCOOH

4.5 E 479.67 480 69 —

6.1 E 493.69 494 70 HCOOH

5.8 E 509.69 510 71 HCOOH

5.6 E 495.66 496 72 HCOOH

6.2 E 497.66 498 73 HCOOH

5.9 E 481.64 482 74 HCOOH

6.0 E 465.64 466 75 HCOOH

6.5 E 481.68 482 76 HCOOH

5.4 E 509.69 510 77 HCOOH

5.4 E 509.69 510 78 HCOOH

6.0 E 497.66 499 79 —

4.9 E 549.76 550 80 2 × HCOOH

5.7 E 495.66 496 81 —

4.6 E 549.76 550 82 2 × HCOOH

5.0 E 519.73 520 83 2 × HCOOH

5.1 E 493.69 494 84 2 × HCOOH

5.12 E 490.69 491 85 2 × HCOOH

6.4 E 493.69 494 86 2 × HCOOH

6.6 E 493.69 494 87 —

4.30 E 478.68 479 88 2 × HCOOH

5.1 E 479.67 480 89 2 × HCOOH

5.3 E 505.70 506 90 2 × HCOOH

4.74 E 504.72 505 91 —

4.7 E 563.78 564 92 —

5.4 E 563.78 564 93 HCOOH

5.0 E 563.78 564 94 HCOOH

5.7 E 563.78 564 95 —

5.1 E 563.78 564 96 —

5.8 E 563.78 564 97 —

6.0 E 591.79 592 98 2 × HCOOH

3.8 E 496.74 497 99 —

3.4 E 591.79 592 100 —

4.3 E 519.73 520 101 —

3.7 E 605.82 606 102 —

4.3 E 605.82 606 103 —

3.2 E 563.78 564 104 —

3.7 E 563.78 564

TABLE 2

MS MW HPLC (calc.) t_(R) free [M + H]⁺ No. salt A-X R³ (min) method base(found) 105 —

2.8 E 587.76 588 106 —

3.5 E 587.76 588 107 —

3.7 E 545.72 546 108

4.3 E 545.72 546 109 —

3.5 E 515.70 516 110 —

3.0 E 601.79 602 111 —

3.8 E 559.75 560 112 —

4.4 E 559.75 560

TABLE 3

MS MW HPLC (calc.) [M + H]⁺ No. salt A-X T t_(R) (min) method free base(found) 113 HCl

5.4 D 542.77 543 114 HCOOH

8.7 E 547.78 548 115 HCl

2.9 B 514.71 515 116 HCl

2.3 B 519.73 521 117 HCOOH

5.1 E 524.16 525 118 HCl

2.4 B 507.70 508 119 HCl

524.16 120 HCl

2.5 B 524.16 524 121 HCl

2.4 B 505.71 507 122 HCOOH

8.9 D 514.72 515 123 HCl

2.5 B 505.71 507 124 HCl

2.5 B 572.82 573 125 HCl

2.4 B 495.74 496 126 HCl

6.3 E 524.16 524 127 HCl

6.1 A 536.17 536 128 HCOOH

9.7 D 550.19 550 129 HCOOH

4.6 E 577.82 578 130 HCOOH

4.8 E 577.82 578 131 HCOOH

6.7 E 586.65 586 132 HCl

2.7 B 558.60 559 133 HCl

2.3 B 489.71 490 134 HCl

2.7 B 557.71 558 135 HCl

2.3 B 496.72 497 136 HCl

2.2 B 558.77 560 137 HCl

2.2 B 560.75 561 138 HCl

5.0 E 514.72 515 139 HCl

2.3 B 549.76 550 140 HCl

2.4 B 519.74 520

TABLE 4

MS MW HPLC (calc.) [M + H]⁺ No. salt R¹ R² t_(R) (min) method free base(found) 141 2 × HCOOH

3.77 E 469.63 470 142 2 × HCl

3.6 F 485.67 486 143 HCOOH

5.62 E 511.71 512 144 HCOOH

5.30 E 485.67 486 145 2 × HCl

3.6 F 509.69 510

TABLE 5

MS MW HPLC (calc.) [M + H]⁺ No. salt NR¹R² t_(R) (min) method free base(found) 146 HCOOH

8.35 D 483.66 485 147 —

2.7 F 469.63 470

TABLE 6

MS MW HPLC (calc.) [M + H]⁺ No. salt R¹ R² t_(R) (min) method free base(found) 148 2 × HCOOH

6.1 E 501.67 502 149 —

2.8 E 521.70 522

TABLE 7

MS MW HPLC (calc.) [M + H]⁺ No. salt R¹ R² t_(R) (min) method free base(found) 150 HCl

4.8 E 500.69 501

The following examples are provided to illustrate the invention and arenot limiting the scope of the invention in any manner.

Synthesis of Example 9 Intermediate 9a

A suspension of CuBr₂ (1071 mg) in EtOAc (10 ml) was heated to refluxand a solution of 5-(3-methoxy-phenyl)-5-oxo-pentanoic acid methyl ester(913 mg) in CHCl₃ was added. The reaction mixture was refluxed overnight. An additional amount of CuBr₂ (300 mg) was added in one portionand the mixture was allowed to reflux for another 4 h. The reactionmixture was filtered over Celite to remove copper salts and the solventwas removed in vacuo to dryness. The residue was purified byflash-chromatography (EtOAc/cyclohexane) to yield the title compound.

Intermediate 9b

To a solution of 6-amino-nicotinic acid (3 g) in DMF/DCM (80/20) wasadded diisoamylamine (4.1 g), EDC (5 g), HOBt (3.52 g) and DIEA (4.54ml). The reaction mixture was stirred at 50° C. over night. The solutionwas evaporated in vacuo to dryness. The residue was redissolved in asmall amount of DMF then buffer (pH 7) was added. The resultingprecipitate was collected, washed with water and dried to yield thetitle compound.

Intermediate 9c

To a solution of intermediate 9b) (1 g) in pyridine (25 ml) was addedp-toluenesulfonylchloride (756 mg) in one portion. The reaction mixturewas heated at 85° C. for 16 h. The solution was evaporated in vacuo todryness and H₂O was added to the residue. The resulting slurry wasstirred for 30 min, then filtered and washed with toluene. The remainingsolid was collected and dried to yield the title compound as a yellowsolid.

Intermediate 9d)

To a warm solution of intermediate 9c) (1781 mg) and DIEA (1.198 ml) inMeCN (50 ml) was added intermediate 9a) (1084 mg). The reaction mixturewas heated at 100° C. for 4 h. The solution was evaporated in vacuo todryness and the residue was purified by flash-chromatography(EtOAc/cyclohexane) to yield the title compound.

Intermediate 9e

Intermediate 9d) (1.372 g) was dissolved in DCM (50 ml) and the reactionwas purged with argon. To this solution TFAA (2 ml) was added and thereaction was allowed to stir for 16 h. The solution was evaporated invacuo to dryness and the residue was purified by flash-chromatography(DCM/MeOH) to yield the title compound as a colorless foam.

Intermediate 9f

Intermediate 9e) (568 mg) was dissolved in THF (40 ml) and methanol (4ml) was added. The solution was heated to reflux and subsequently sodiumborohydride (87 mg) was added. Further sodium borohydride was added inseveral portions and refluxing continued. The reaction was stopped withacetone and the solvent removed in vacuo. The residue was purified byflash chromatography (DCM/MeOH 98:2) to yield the title compound.

Intermediate 9g

A solution of intermediate 9f) in dry DCM (10 ml) was purged with argonand cooled to 0° C. TEA (170 μl) and mesylchloride (95 μl) were added tothis solution and the reaction mixture was allowed to warm up. Stirringwas continued for 3 h. The reaction mixture was washed with H₂O andsaturated NaHCO₃ solution. The organic layer was dried over Na₂SO₄ andevaporated in vacuo to dryness to yield the title compound, which wasused in the next step without further purification.

Example 9

To a solution of pyrrolidine (168 mg) in dry MeCN (5 ml) was added asolution of intermediate 9 g) (86 mg) in dry MeCN. The reaction washeated to 75° C. for 14 h. The solution was evaporated in vacuo todryness and the residue was purified by preparative HPLC to yield thetitle compound as a colorless solid.

Synthesis of Example 17 Intermediate 17a

The synthesis was performed as described for intermediate 9e).

Intermediate 17b

To a solution of intermediate 17a) (370 mg) in THF (15 ml) was added a2M solution of lithium hydroxide in water (0.74 ml) at 0° C.Subsequently the ice bath was removed and the reaction allowed to stirat ambient temperature for 2 days. The mixture was diluted with ethylacetate and brine and the pH adjusted to pH 6 with a solution of 3%citric acid. After separation of the layers, the organic layer waswashed with brine and dried over sodium sulfate. The solvent was removedunder reduced pressure to yield the title compound that was used in thenext step without further purification.

Intermediate 17c

Intermediate 17b) (315 mg) was dissolved in THF (20 ml) andcarbonyldiimidazole (162 mg) was added. The mixture was stirred atambient temperature for 1 h before cooled to 0° C. Sodium borohydride(38 mg) in water was added and stirring continued for another 10 min.The reaction was quenched with acetone and the solvent removed in vacuo.The residue was taken up in ethyl acetate and water. After separation ofthe layers, the organic layer was washed with a solution of 5% citricacid, saturated sodium bicarbonate solution and brine. After drying oversodium sulfate the solvent was removed in vacuo and the residue purifiedby flash chromatography (DCM/MeOH) to yield the title compound.

Intermediate 17d

Intermediate 17c) (100 mg) was dissolved in dichloromethane (10 ml) andat 0° C. mesylchloride (0.026 ml) and triethylamine (0.046 ml) wereadded. The ice bath was removed and the mixture stirred at ambienttemperature before additional mesylchloride (0.007 ml) and triethylamine(0.012 ml) were added and stirring continued for another hour. Themixture was diluted with dichloromethane and washed with water/saturatedsodium bicarbonate and water. The organic layer was dried over sodiumsulfate and the solvent removed in vacuo to yield the title compoundthat was used in the next step without further purification.

Example 17

To a solution of pyrrolidine (78 mg) in dry MeCN (1.5 ml) was added asolution of intermediate 17d) (55 mg) in dry acetonitrile. The reactionwas heated to 50° C. overnight. The mixture was evaporated in vacuo todryness and the residue was purified by flash chromatography (DCM/MeOH)to yield the title compound. The free base was transformed into thecorresponding HCl salt.

Synthesis of Example 21 Intermediate 21a

To a solution of intermediate 9e) (300 mg) in THF (12 ml) was added a 2Msolution of lithium hydroxide in water (0.61 ml) at 0° C. Subsequentlythe ice bath was removed and the reaction allowed to stir at ambienttemperature overnight. The mixture was diluted with ethyl acetate andbrine and the pH adjusted to pH 6 with a solution of 3% citric acid.After separation of the layers, the organic layer was washed with brineand dried over sodium sulfate. The solvent was removed under reducedpressure to yield the title compound that was used in the next stepwithout further purification.

Intermediate 21b

Intermediate 21a) (275 mg) was dissolved in dichloromethane andcarbonyldiimidazole (102 mg) was added. The mixture was stirred atambient temperature for 30 min before N,O-dimethylhydroxylaminehydrochloride (62 mg) and diisopropylethlyamine (0.110 ml) were addedsubsequently. Stirring was continued overnight. The mixture was dilutedwith dichloromethane and the organic phase washed with a solution of 5%citric acid, sodium bicarbonate solution and brine before drying oversodium sulfate and removing the solvent in vacuo. Purification by flashchromatography (DCM/MeOH) yielded the title compound.

Intermediate 21c

To a solution of intermediate 21b) (100 mg) in dry tetrahydrofurane wasadded a solution of methyllithium (1.5 M in diethylether, 0.12 ml) at−78° C. The mixture was stirred for 30 min before hydrolyzing withsaturated ammonium chloride solution. After dilution with diethylether,the layers were separated and the aqueous layer extracted twice withdiethylether. Combined organic layers were washed with brine, dried oversodium sulfate and the solvent removed in vacuo. Purification by flashchromatography led to the title compound.

Example 21

Intermediate 21c) (65 mg) and pyrrolidine (0.013 ml) were dissolved indichloroethane (2 ml) and subsequently glacial acetic acid (0.008 ml)and sodium triacetoxyborohydride (42 mg) were added. The mixture wasstirred at ambient temperature for 3 days. The solvent was removed underreduced pressure and the residue purified by flash chromatography(DCM/MeOH) to yield the title compound. The free base was transformedinto the HCl salt.

Synthesis of Example 25 Example 25

To a solution of Example 17 (407 mg) in tert. butyl alcohol (8 ml) finepowder of potassium hydroxide (240 mg) was added and the mixture heatedto 70° C. for 4 hours. Then the mixture was partitioned between brineand ethyl acetate. The aqueous phase was extracted three times withethyl acetate. The combined organic layers were dried over sodiumsulfate. The solvent was removed under reduced pressure to yield thetitle compound which was purified by preparative HPLC.

Synthesis of Example 27 Intermediate 27a

Copper bromide (547 mg) was suspended in ethyl acetate (13 ml) andheated to reflux. Then 4′-cyano-3-(1,3-dioxan-2-yl) propiophenone (500mg) in chloroform (13 ml) was added. The reaction mixture was refluxedfor 2 h. Another 340 mg of copper bromide were added in two portionsfollowed by 2 hours of refluxing. The mixture was stirred overnight atroom temperature and subsequently filtered through Celite. The solventswere evaporated under reduced pressure and the product purified bychromatography.

Intermediate 27b

A mixture of tosylate intermediate 9c) (700 mg) anddiisopropylethylamine (0.52 ml) in acetonitrile (20 ml) was heated to50° C. Intermediate 27a) (480 mg) in acetonitrile was then added and thereaction mixture stirred at 50° C. for 30 min and at room temperatureovernight. The solvent was removed under reduced pressure. The mixturewas purified by flash chromatography to yield the title compound.

Intermediate 27c

Intermediate 27b) (620 mg) was dissolved in dry dichloromethane (16 ml).The mixture was cooled to 0° C. with an ice bath. Then trifluoroaceticanhydride (1.62 ml) was added. The mixture was stirred at 0° C. for 30minutes and then at room temperature for 2 hours.

The solvent was removed under reduced pressure. The product intermediate27c) was used without purification for the next step.

Intermediate 27d

Intermediate 27c) (460 mg) was dissolved in tetrahydrofurane (16 ml) andthe solution cooled to 0° C. 6M HCl (0.46 ml) was added and the reactionmixture then stirred at 60° C. overnight. Another 3 equivalents of HCl6N were added and the mixture continued to stir at 60° C. The mixturewas neutralized with sodium carbonate and the product was extracted withethyl acetate. The organic phase was dried over sodium sulfate. Thesolvent was removed under reduced pressure and the mixture purified byflash chromatography to yield the title compound.

Example 27

Intermediate 27d) (19 mg) was dissolved in dichloroethane (0.3 ml),1-methylpiperazine (5 μl) was added and the reaction mixture stirred for30 min. After addition of sodium triacetoxyborohydride (12 mg) themixture was stirred at room temperature overnight. Water was added andthe aqueous phase was extracted twice with dichloromethane. The combinedorganic layers were dried over sodium sulfate and the solvent wasremoved under reduced pressure. The title compound was purified bypreparative HPLC.

Synthesis of Example 47 Intermediate 47a

Under argon, to a stirring suspension of copper(II) bromide (9.523 g) inethyl acetate (100 ml) was added 2-(5-chlorovaleryl)oxazole (4.000 g) inchloroform (100 ml). The resulting mixture was stirred at refluxtemperature overnight. The reaction mixture was filtered through Celiteand the filtrate was evaporated to dryness. The crude product waspurified by column chromatography.

Intermediate 47b

At 50° C. to a stirring solution of intermediate 47a) (2665 mg) inacetonitrile (75 ml) was added DIEA (3658 μl). The obtained solution wasstirred for 15 minutes then intermediate 9c) (4532 mg) in acetonitrile(75 ml) was added. The obtained solution was stirred at 50° C. for 3 h.Volatiles were removed and the product was purified by columnchromatography.

Intermediate 47c

At 0° C., to a stirring solution of intermediate 47b) (4.65 g) in dryDCM (45 ml) was added TFAA (5 ml). The reaction mixture was then allowedto warm to RT and stirred for 3 h. The reaction mixture was neutralizedwith NaHCO₃ sat. and then phases were separated. The organic layer wasextracted twice with NaHCO₃ sat. The combined aqueous layer wasextracted back with DCM. The combined organic layer was washed withbrine, dried over Na₂CO₃, filtered and volatiles were removed. The crudeproduct was purified by column chromatography.

Example 47

Intermediate 47c) (1068 mg) was dissolved in acetonitrile (100 ml).Pyrrolidine (2003 μl) was added and the reaction mixture was stirred at70° C. for 8 h. Volatiles were removed and the crude product waspurified with preparative LC-MS. The purified compound was taken up withethyl acetate and washed with saturated aqueous sodium bicarbonatesolution. The aqueous phase was extracted three times with ethylacetate. The combined organic layer was washed with brine, dried oversodium sulfate and the solvent was removed. The obtained oil wasdissolved in ethyl acetate (10 ml) and 1 M HCl in diethyl ether (2 ml)was added. Volatiles were removed and the product was obtained in formof an off-white powder.

Synthesis of Example 50 Example 50

Example 25 (422 mg) was dissolved in concentrated hydrochloric acid andrefluxed for 2 hours. The solvent was removed under reduced pressure toyield the title compound which was purified by preparative HPLC.

Synthesis of Example 54 Intermediate 54a

A mixture of 2-(3-methoxy-phenyl)-imidazo[1,2-a]pyridine-6-carboxylicacid methyl ester (1000 mg), methacrolein (990 mg), acetic anhydride(5.5 ml) and glacial acetic acid (14.5 ml) was heated in the microwaveat 180° C. for 75 minutes. Then the volatiles were removed under reducedpressure. Methanol and 1N aqueous sodium bicarbonate solution were addedand the mixture stirred for 2 h. The solvents were removed, and theresidue dissolved in ethyl acetate and water. The organic layer wasseparated and dried over sodium sulfate. The solvent, was removed underreduced pressure to yield the title compound which was taken to the nextstep without further purification.

Intermediate 54b

Intermediate 54a) (450 mg) was dissolved in dichloromethane (27 ml),pyrrolidine (0.11 ml) was added and the mixture stirred for 30 min atambient temperature. Then sodium triacetoxyborohydride (360 mg) wasadded and the reaction was stirred overnight. Water was added and theaqueous phase was extracted twice with dichloromethane. The combinedorganic layers were dried over sodium sulfate and the solvent removedunder reduced pressure. The product was purified by flashchromatography.

Intermediate 54c

Intermediate 54b) (78 mg) was dissolved in tetrahydrofurane (3.5 ml) andcooled to 0° C. Then lithium hydroxide (0.19 ml, 2N in water) was addedand the mixture was left to reach room temperature and stirred for 2days. Ethyl acetate and brine were added. The white precipitate wasdissolved by adding drops of citric acid (5%). The organic layer wasseparated and dried over sodium sulfate. The solvent was removed underreduced pressure to yield intermediate 54c).

Example 54

Intermediate 54c) (38 mg) was dissolved in DMF (5 ml). ThenO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU, 44 mg), diisopropylethylamine (20 μl) anddiisoamylamine (24 μl) were added and the mixture stirred overnight atambient temperature. Solvents were evaporated. The product was thendissolved in ethyl acetate. The organic layer was washed with brine,then with saturated sodium bicarbonate and with brine again. The organiclayer was dried over sodium sulfate, filtered and the solventevaporated. The product was purified by preparative HPLC to yieldExample 54.

Synthesis of Example 58 Intermediate 58a

At 0° C., EDC (1608 mg) was added to 5-methyl-pyridine-2-carboxylic acid(1000 mg) in DCM (25 ml). The reaction mixture was stirred at 0° C. for30 min and then N,O -dimethylhydroxylamine hydrochloride (818 mg) wasadded, followed by NMM (922 μl). The reaction was allowed to warm to RTand stirred over night. The reaction mixture was diluted with DCM (25ml), and then extracted with NaHCO₃ sat. (2×25 ml). The aqueous layerwas extracted back with DCM (25 ml). The combined organic layer waswashed with brine, dried over Na₂SO₄, filtered and solvents wereremoved. The crude product was purified by column chromatography.

Intermediate 58b

At −78° C., under argon atmosphere, to a stirring solution ofintermediate 58a) (1270 mg) in dry THF (10 ml) was carefully addedmethyl lithium (1.6M in Et₂O, 13.2 ml). The reaction mixture was stirredat −78° C. for 90 minutes, and then hydrolyzed with NH₄Cl sat. (10 ml).The reaction mixture was diluted with diethyl ether (50 ml). The aqueouslayer was extracted back with diethyl ether (2×10 ml). The combinedorganic layer was washed with brine, dried over Na₂SO₄, filtered andsolvent was carefully removed. The product was purified by Kugelrohrdistillation (10 mbar, 130° C.).

Intermediate 58c

At RT, to a stirring solution of intermediate 58b) (541 mg) in AcOH (10ml) was added 33% HBr in AcOH (2 ml) and then bromine (53 μl). After 30minutes additional bromine (50 μl) was added and the reaction mixturestirred for 90 minutes. The reaction mixture was concentrated in vacuoand then poured in a saturated aqueous NaHCO₃ solution. It was extractedwith three times with ethyl acetate. The combined organic layer wasdried over Na₂SO₄, filtered and solvents were carefully removed. Thecrude product was purified by column chromatography.

Intermediate 58d

Intermediate 58c) (350 mg) and intermediate 9b) (522 mg) were dissolvedin MeCN (10 ml) and then heated to 180° C. for 30 min using microwaveirradiation. Volatiles were removed and the crude product was purifiedby column chromatography.

Intermediate 58e

Acroleine (233 μl) was added to a solution of intermediate 58d) (381 mg)in glacial acetic acid (6 ml) followed by acetic anhydride (2 ml) andthe mixture was heated at 180° C. in a microwave reactor for 30 min. Thereaction mixture was poured in a mixture of saturated aqueous sodiumbicarbonate solution (100 ml) and saturated aqueous sodium carbonatesolution (50 ml) to reach a basic pH and then extracted with ethylacetate (2×50 ml). The organic layer was washed with brine, dried onNa₂SO₄, filtered and the solvent was removed. A 1M solution of sodiumbicarbonate in water (10 ml) was added to the crude product in methanol(50 ml). The reaction mixture was stirred at RT over night. The reactionmixture was concentrated in vacuum and then partitioned betweensaturated aqueous NaHCO₃ solution and DCM. The aqueous layer wasextracted twice with DCM. The combined organic layer was washed withbrine, dried over Na₂SO₄, filtered, and solvent was removed.

Example 58

Intermediate 58e) (83 mg) and 2M dimethylamine in THF (463 μl) weredissolved in 1,2-dichloroethane (5 ml). After 1 h stirring at RT, sodiumtriacetoxyborohydride (782 mg) was added. The mixture was stirred atambient temperature overnight. The reaction mixture was extracted with1M NaHCO₃ (2×2 ml). The aqueous layer was extracted back with DCE (2ml). The combined organic layer was washed with brine, dried overNa₂SO₄, filtered, and evaporated to dryness in vacuum. The crude productwas purified with preparative LC-MS.

Synthesis of Example 59 Intermediate 59a

Under argon, to a stirring suspension of copper(II)-bromide (19.36 g) inethyl acetate (200 ml) was added 6-chloro-3-(5-chlorovaleryl)-pyridine(10.06 g) in chloroform (200 ml). The resulting mixture was stirred atreflux for 20 h. The reaction mixture was filtrated on Celite andconcentrated in vacuum.

The residue of the filtartion was washed with acetonitrile and thefiltrate was concentrated in vacuum. The residue was up taken in ethylacetate (500 ml) and washed with saturated sodium bicarbonate solution(500 ml). The aqueous layer was extracted with twice with ethyl acetate.The organic layers were combined with the first isolated batch, washedwith saturated sodium bicarbonate solution, water and brine, dried overMgSO₄, filtered and the solvent was removed under reduced pressure.

Intermediate 59b

To a solution of 6-aminonicotinic acid methyl ester (20.09 g) in drypyridine (400 ml) under argon atmosphere was added tosyl chloride (28.94g). The reaction mixture was stirred at 85° C. for 16 h. The solvent wasremoved under reduced pressure, the residue taken up with water andstirred for 2 h. A beige precipitate was formed. It was filtered, washedtwice with water and dried over Sicapent.

Intermediate 59c

A mixture of intermediate 59b) (9.74 g) and intermediate 59a) (10.24 g)in acetonitrile (300 ml) was treated with ethyldiisopropylamine (6654μl) and stirred at 50° C. overnight. The solvent was removed underreduced pressure. The product was purified with flash chromatography.

Intermediate 59d

Intermediate 59c) (15.07 g) was dissolved in dry DCM (180 ml) and cooledto 0° C. Trifluoroacetic acid anhydride (20 ml) was added and thereaction mixture was allowed to stir at room temperature overnight. Thereaction mixture was diluted with DCM (200 ml) and carefully extractedwith sat. sodium bicarbonate solution. The aqueous layer was extractedtwice with DCM. The combined organic layer was washed with brine, driedover sodium sulfate and the solvent was removed under reduced pressure.

Intermediate 59e

Intermediate 59d) (5.0 g), acetonitrile (120 ml) and pyrrolidine (10.9ml) were stirred at 70° C. overnight. The solvent was removed underreduced pressure. The product was triturated with acetone, filtered anddried in a vacuum oven overnight.

Intermediate 59f

Intermediate 59e) (4.6 g) was dissolved in 3 M HCl in water (150 ml) andthe reaction mixture was stirred at 120° C. for 36 h. The solvent wasremoved under reduced pressure, the residue co-evaporated twice withtoluene and the product was dried on high vacuum for 2 d. The productwas used as such for the next step without further purification.

Example 59

Intermediate 59f) (1000 mg) was dissolved in DMF (10 ml) and then EDC(525 mg), HOAt (373 mg) and DIEA (1431 μl) were added. The reactionmixture was stirred for 1 h. Diisoamylamine (562 μl) was added and thereaction mixture was stirred overnight. Volatiles were removed and thenthe residue was dissolved in of ethyl acetate (200 ml). The organiclayer was washed with NaHCO₃ sat. (2×100 ml) then the combined aqueouslayers were extracted back with ethyl acetate (100 ml). The combinedorganic layer was washed with brine, dried over Na₂SO₄, filtrated andthe solvent was removed under reduced pressure. The crude product waspurified with preparative LC-MS.

Synthesis of Example 64 Example 64

Example 50 (200 mg),O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU, 185 mg) and diisopropylethylamine (1.95 ml)in dimethylformamide (4 ml) were stirred for 15 minutes at ambienttemperature before a solution of methyl amine 2N in tetrahydrofurane(0.28 ml) was added and the stirring continued overnight. Ethyl acetatewas added. The organic layer was washed with saturated sodiumbicarbonate solution and brine and dried over sodium sulfate. Thesolvent was removed under reduced pressure to yield the title compoundwhich was purified by preparative HPLC.

Synthesis of Example 79 Intermediate 79a

At 50° C. to a stirring suspension of intermediate 59a) (679 mg) inacetonitrile (15 ml) was added DIEA (806 μl). The obtained solution wasstirred for 10 minutes then intermediate 9c) (993 mg) in acetonitrile(15 ml) was added. The obtained solution was stirred at 50° C. for 2 h.Solvents were removed and the obtained oil was purified by columnchromatography.

Intermediate 79b

At 0° C., to a stirring solution of intermediate 79a) (1.35 g) in dryDCM (18 ml) was added TFAA (2 ml). The reaction mixture was then allowedto warm to RT and stirred overnight. Volatiles were removed and theobtained oil was purified by column chromatography.

Intermediate 79c

Intermediate 79b) (100 mg), acetonitrile (5 ml) and pyrrolidine (167 μl)were stirred at 70° C. overnight. The solvent was removed under reducedpressure. The product was purified by column chromatography.

Example 79

To a suspension of sodium hydride (31 mg) in DMF (5 ml) was addedethyleneglycol (22 μl) under argon atmosphere. The reaction mixture wasstirred at room temperature for 30 min and then intermediate 79c) (70mg) in DMF (5 ml) was added. The mixture was stirred at 140° C.overnight. The mixture was cooled and hydrolyzed with water. Solvent wasevaporated and the residue taken up in ethyl acetate. The organic layerwas extracted with water and brine and the solvent was removed underreduced pressure. The crude product was purified using preparativeLC-MS.

Synthesis of Example 90 Intermediate 90a

2-(2-Chloro-pyridin-3-yl)-3-(3-pyrrolidin-1-yl-propyl)-imidazo[1,2-a]pyridine-6-carboxylicacid bis-(3-methyl-butyl)-amide (100 mg) and benzyl amine (0.5 ml) wereheated in the microwave at 150° C. for 2 h. The mixture was purified byflash chromatography to yield the title compound.

Example 90

Trifluoromethanesulfonic acid (300 mg) was added dropwise tointermediate 90a) (78 mg) in dry dichloromethane (1.5 ml) at 0° C. Thenthe mixture was heated to 40° C. for 3 hours. Again the mixture wascooled to 0° C. and another 300 mg of trifluoromethanesulfonic acid wereadded followed by heating to reflux for 2 h. Solvents were evaporatedunder reduced pressure. The title compound was obtained afterpurification by preparative HPLC.

Synthesis of Examples 91 and 92 Examples 91 and 92

Example 59) (100 mg) was dissolved in acetone (5 ml) and then potassiumcarbonate (41 mg) and 3-bromo-1-propanol (20 μl) were added. Thereaction mixture was stirred at 60° C. overnight, filtered and thesolvent was removed under reduced pressure. The products were separatedwith preparative LC-MS.

Synthesis of Example 98 Intermediate 98a

Prior to be used, δ-valerolactone was distillated under reduce pressure(bp 106° C./22 mbar). To a stirring suspension of sodium hydride (60% inoil, 2.66 g) in dry toluene (100 ml) at reflux was added dropwise amixture of methyl tetrahydro-2H-pyran-4-carboxylate (8.87 ml) andδ-valerolactone (6.34 g) in dry toluene (50 ml). After addition, thereaction mixture was stirred at reflux temperature over night. Aftercooling to room temperature, the reaction mixture was poured in ice coldwater (300 ml). Solid in the flask was recovered with water (150 ml) andtoluene (50 ml). After phase separation, the aqueous layer was acidifiedusing AcOH (5 ml) and extracted with ethyl acetate (3×150 ml). Thecombined organic layer was washed with brine, dried over Na₂SO₄,filtered and volatiles were removed. The crude product was purified bycolumn chromatography.

Intermediate 98b

Intermediate 98a) (1.86 g) was stirred in concentrated hydrochloric acid(10 ml) at 80° C. for 1 h. The reaction mixture was poured in Na₂CO₃sat. (300 ml) and extracted with DCM (3×100 ml). The combined organiclayer was washed with brine, dried over Na₂SO₄, filtered and volatileswere removed.

Intermediate 98c

Under argon, to a stirring suspension of copper(II) bromide (1965 mg) inethyl acetate (25 ml) was added intermediate 98b) (934 mg) in chloroform(25 ml). The resulting mixture was stirred at reflux overnight. Thereaction mixture was filtrateted through Celite and the Celite pad wasthoroughly washed with ethyl acetate. The organic layer was extractedtwice with NaHCO₃ sat. The aqueous layer was extracted back with ethylacetate. The combined organic layer was washed with brine, dried overNa₂SO₄, filtered and volatiles were removed.

Intermediate 98d

At 50° C. to a stirring suspension of 9c) (1994 mg) in acetonitrile (50ml) was added DIEA (1610 μl). The obtained solution was stirred at 50°C. for 15 minutes then intermediate 98c) (1.25 g) in acetonitrile (50ml) was added. The obtained reaction mixture was stirred at 50° C. overnight. Volatiles were removed and the crude was purified by columnchromatography.

Intermediate 98e

Under argon atmosphere, to a solution of intermediate 98d) (525 mg) inDCE (9 ml) was added TFAA (1 ml), and the reaction mixture was stirredat RT for 4 days. Additional TFAA (1 ml) and DCE (9 ml) were added andthe reaction mixture heated to reflux over night. Volatiles were removedand the residue was taken up in ethyl acetate (50 ml). The organic layerwas extracted twice with Na₂CO₃ sat. (25 ml). The combined aqueous layerwas extracted back with ethyl acetate (25 ml). The combined organiclayer was washed with brine, dried over Na₂SO₄, filtered, and volatileswere removed. The crude product was purified by column chromatography.

Example 98

To a stirring solution of intermediate 98e) (85 mg) in MeCN (10 ml) wasadded pyrrolidine (172 μl) and the reaction mixture was stirred in asealed tube at 50° C. for 2 d. Volatiles were removed and the crudeproduct was purified by preparative LC-MS.

Synthesis of Example 109 Intermediate 109a

To a solution of cyclopropylacetic acid (2002 mg) in DCM (100 ml) at 0°C. was added EDC (3834 mg) and HOBt (3063 mg). The reaction mixture wasstirred at 0° C. for 30 min. Cyclopropylethylamine (1703 mg) and DIEA(10.45 ml) were added and the reaction mixture was stirred at roomtemperature overnight. The reaction mixture was extracted with 1.0 N HCl(100 ml), sat. NaHCO₃ (100 ml), water (100 ml) and brine (100 ml). Theorganic layer was dried over Na₂SO₄ and evaporated in vacuo to dryness.

Intermediate 109b

A solution of intermediate 109a) (2448 mg) in anhydrous THF (40 ml) wasadded dropwise under argon atmosphere to a suspension of lithiumaluminum hydride (1389 mg) in anhydrous THF (60 ml) at room temperature.The reaction mixture was heated to reflux temperature and stirred foranother 2 days. The reaction mixture was hydrolyzed by addition of 10%aqueous KOH (100 ml) at 0° C. After stirring for 20 min at roomtemperature the reaction mixture was filtered and the solid was washedwith diethyl ether (100 ml). The biphasic filtrate was transferred intoa separation funnel and the organic layer was washed with water andbrine. The combined aqueous layer was washed twice with diethyl ether(2×100 ml). The combined organic layer was washed with brine, dried overmagnesium sulfate and the solvent was removed under reduced pressure.

Intermediate 109c

Intermediate 59d) (2.0 g), acetonitrile (30 ml) and 2-methyl-pyrrolidine(1.27 ml) were stirred at 70° C. overnight. DIEA (500 μl) was added andthe mixture was stirred at 70° C. for 20 h. The solvent was removedunder reduced pressure and the residue taken up with ethyl acetate andwashed twice with saturated sodium bicarbonate solution, water andbrine. The organic layer was dried over sodium sulfate, filtered and thesolvent was removed under reduced pressure. The crude product waspurified by column chromatography.

Intermediate 109d

Intermediate 109c) (1.7 g) was dissolved in 3 M HCl in water (100 ml)and the reaction mixture was stirred at 120° C. for 24 h. The solventwas removed under reduced pressure, the residue co-evaporated twice withtoluene and the product was dried on high vacuum for 3 h andsubsequently in an oven at 40° C. under reduced pressure for 3 d. Theproduct was used as such for the next step without further purification.

Example 109

Intermediate 109d) (600 mg) was dissolved in DMF (5 ml) and then EDC(299 mg), HOAt (212 mg) and DIEA (815 μl) were added. The reactionmixture was stirred for 1 h. Intermediate 109b) (239 mg) was added andthe reaction mixture was stirred overnight. Volatiles were removed andthen the residue was dissolved in of ethyl acetate (100 ml). The organiclayer was washed with NaHCO₃ sat. (2×50 ml) then the combined aqueouslayers were extracted back with ethyl acetate (50 ml). The combinedorganic layer was washed with brine, dried over Na₂SO₄, filtrated andthe solvent was removed under reduced pressure. The crude product waspurified by preparative LC-MS.

Synthesis of Example 110 Example 110

Example 109 (230 mg) was dissolved in acetone (7 ml) and then cesiumcarbonate (222 mg) and 2-bromoethyl acetate (55 μl) were added. Thereaction mixture was stirred at 60° C. overnight, filtered and thesolvent was removed under reduced pressure. The N- and O-alkylatedproducts were separated by preparative LC-MS.

Synthesis of Examples 111 and 112 Examples 111 and 112

A mixture of Example 110 and the O-alkylated side-product (crude productbefore purification) (116 mg) was dissolved in THF (10 ml) and cooled to0° C. Lithium hydroxide monohydrate (30 mg) in water (2 ml) was addedand the reaction mixture was stirred at 0° C. for 30 min and at roomtemperature for 2.5 h. The reaction mixture was concentrated and thenpartitioned between ethyl acetate and water. The aqueous layer wasextracted three times with ethyl acetate. The combined organic layer waswashed with brine, dried over sodium sulfate and the solvent was removedunder reduced pressure. The products were separated by preparativeLC-MS.

Synthesis of Example 114 Intermediate 114a

To a solution of 6-amino-N,N-bis-(3-methyl-butyl)-nicotinamide (100 mg)in MeCN (2 ml) was added 2-bromo-3′-methoxyacetophenone in MeCN (2 ml)and the mixture was heated at 170° C. under microwave irradiation for 40min. The solvent was evaporated and the crude mixture was purified byflash chromatography (EtOAc/cyclohexane) to yield the title compound.

Example 114

A solution of 4-dimethylamino-piperidine (14.1 mg) in HOAc andformaldehyde (37% aqueous solution, 8.2 μl) was added to intermediate114a) (30 mg) in HOAc and the mixture was heated at 60° C. for 16 h.After evaporation of the solvent the crude reaction mixture was purifiedby preparative HPLC to yield the title compound.

Synthesis of Example 119 Intermediate 119a

To a solution of 6-amino-N,N-bis-(3-methyl-butyl)-nicotinamide (1000 mg)in MeCN (10 ml) was added 2-bromo-4′-chloroacetophenone in MeCN (10 ml)and the mixture was heated at 160° C. under microwave irradiation for 15min. Upon cooling a precipitate formed that was collected and dried toyield the title compound.

Example 119

A solution of [1,4]diazepane-1-carboxylic acid tert-butyl ester (22.3mg) in HOAc and formaldehyde (37% aqueous solution, 13.5 μl) was addedto intermediate 119a) (30 mg) in HOAc and the mixture was heated at 60°C. for 16 h. After evaporation of the solvent the crude reaction mixturewas purified by flash chromatography (DCM/MeOH). The resultingBoc-protected intermediate was then treated with 4M HCl/dioxane for 1 hto yield the title compound.

Synthesis of Example 143 Intermediate 143a

2-Cyclopropyl-ethylamine hydrochloride (700 mg) was suspended indichloromethane (14 ml). The solution was cooled to 0° C., followed byaddition of isovaleryl chloride (0.84 ml) and triethylamine (1.60 ml).The reaction was allowed to warm to room temperature and the reactionmixture was stirred for 4 h. The solvent was evaporated and the residuewas partitioned between ethyl acetate (50 ml) and NaHCO₃ sat. (40 ml).The aqueous layer was extracted twice with ethyl acetate (50 ml) and thecombined organic phases were washed with brine (40 ml). The organiclayer was dried over Na₂SO₄, filtrated and the solvent was removed underreduced pressure. The crude product was purified with preparative LC-MS.

Intermediate 143b

Intermediate 143a) (838 mg) was treated with borane-tetrahydrofurancomplex (1M solution in THF, 14.9 ml) and the reaction mixture wasstirred under reflux for 6 h. Then the reaction mixture was cooled to 0°C. and methanol (7 ml) was added carefully. The reaction mixture wasrefluxed for 5 h and cooled to 0° C. Di-tert-butyl dicarbonate dissolvedin DCM (7 ml) was added and the reaction mixture was stirred at roomtemperature over night. Volatiles were removed and the residue wasdissolved in ethyl acetate (100 ml). The organic layer was washed withwater (60 ml) and brine (60 ml). The organic layer was dried overNa₂SO₄, filtrated and the solvent was removed under reduced pressure.The crude product was used without other purification.

Intermediate 143c

Intermediate 143b) (1.26 g) was dissolved in DCM (30 ml) and 4 M HCl indioxane (1.48 ml) was added. The reaction mixture was stirred at roomtemperature for 14 h. The solvent was evaporated and the resulting whitesolid was triturated with ether and the product was collected byfiltration, washed with ether and dried on the high-vacuum. The solidwas used without further purification.

Intermediate 143d

Under argon, to a stirring suspension of copper(II)-bromide (3.62 g) inethyl acetate (60 ml) was added 5-chloro-1-(4-cyanophenyl)-1-oxopentane(3.00 g) in chloroform (60 ml). The resulting mixture was stirred atreflux over night. Additional copper(II)-bromide (0.60 g) was added andthe reaction was refluxed for 3 h. The reaction mixture was filtrated onCelite, washed with ethyl acetate and concentrated in vacuum. Theproduct was purified with flash chromatography.

Intermediate 143e

Intermediate 143d) (3.00 g) was dissolved in acetonitrile (80 ml).Ethyldiisopropylamine (3.2 ml) was added and the reaction mixture washeated at 85° C. Intermediate 59b) (2.80 g) dissolved in acetonitrile(20 ml) was added and the reaction mixture was refluxed for 1 h. Thesolvent was removed under reduced pressure. The product was purifiedwith flash chromatography.

Intermediate 143f

Intermediate 143e) (4.67 g) was dissolved in dry DCM (90 ml) and cooledto 0° C. Trifluoroacetic acid anhydride (12 ml) was added and thereaction mixture was allowed to stir at room temperature for 6 h. Thesolvent was removed under reduced pressure. The residue was dissolved inethyl acetate (200 ml) and was poured in a sat. sodium bicarbonatesolution. The obtained white precipitate was filtrated off, washed withwater and dried under high vacuum.

Intermediate 143g

Intermediate 143f) (1.50 g), acetonitrile (40 ml) and pyrrolidine (3.5ml) were stirred at 70° C. for 6 h. Half of the solvent was removedunder reduced pressure and the remained solution was cooled on an icebath for 2 h. The obtained solid was filtrated and washed with cooledacetonitrile. The product was dried under high vacuum.

Intermediate 143h

Intermediate 143g) (313 mg) was dissolved in THF (10 ml) and 2 M LiOH inwater (0.92 ml) was added. The reaction mixture was stirred at roomtemperature over night. Additional THF (1.5 ml) and 2 M LiOH in water(0.1 ml) were added and the reaction mixture was stirred at roomtemperature for 3 h. The obtained solid was filtrated, washed withcooled THF and dried on high vacuum. The product was used as such forthe next step without further purification.

Example 143

Intermediate 143h) (40 mg) was dissolved in DMF (3 ml) and then HATU (49mg), DIEA (22 μl) and intermediate 143c) (23 mg) were added. Thereaction mixture was stirred for 1 h. The reaction was not completed,therefore additional intermediate 143c) (10 mg) and DIEA (22 μl) wereadded and the reaction mixture was stirred for 2 h. Volatiles wereremoved and then the residue was dissolved in ethyl acetate (50 ml). Theorganic layer was washed with brine (40 ml), NaHCO₃ sat. (40 ml) andbrine (40 ml). The organic layer was dried over Na₂SO₄, filtrated andthe solvent was removed under reduced pressure. The crude product waspurified with preparative LC-MS.

Biological Assays A. Binding Assay

A membrane binding assay is used to identify competitive inhibitors offluorescence labeled NDP-alpha-MSH binding to HEK293 cell membranepreparations expressing human melanocortin receptors.

The test compound or unlabeled NDP-alpha-MSH is dispensed at varyingconcentrations to a 384 well microtiter plate. Fluorescence labeledNDP-alpha-MSH is dispensed at a single concentration, followed byaddition of membrane preparations. The plate is incubated for 5 h atroom temperature.

The degree of fluorescence polarization is determined with afluorescence polarization microplate reader.

B. Functional Assay

Agonistic activity of human melanocortin receptors is determined in ahomogeneous membrane based assay. Competition between unlabeled cAMP anda fixed quantity of fluorescence labeled cAMP for a limited number ofbinding sites on a cAMP specific antibody is revealed by fluorescencepolarization.

The test compound or unlabeled NDP-alpha-MSH is dispensed at varyingconcentrations to a 384 well microtiter plate. Membrane preparationsfrom HEK293 cells expressing the human melanocortin receptors are added.After a short preincubation period, an appropriate amount of ATP, GTPand the cAMP antibody is added and the plate is further incubated beforethe fluorescence labeled cAMP conjugate is dispensed. The plate isincubated for 2 h at 4° C. before it is read on a fluorescencepolarization microplate reader. The amount of cAMP produced as aresponse to a test compound is compared to the production of cAMPresulting from stimulation with NDP-alpha-MSH.

Representative compounds of the present invention were tested and foundto bind to the melanocortin-4 receptor. These compounds were generallyfound to have IC₅₀ values less than 2 μM. Representative compounds ofthe present invention were also tested in the functional assay and foundgenerally not to activate the melanocortin-4 receptor.

TABLE 8 Biological data for the examples of the invention hMC-4R hMC-4Rbinding functional % activation assay assay functional Example IC₅₀/μMEC₅₀/μM assay SHU-9119 a — 7 NDP-α-MSH a a 100  1 b — 0  2 a — 0  3 b —0  4 b — 0  5 b — 0  6 a — 0  7 b — 0  8 a — 0  9 a — 0 10 c — 0 11 a —0 12 a — 0 13 c — 0 14 a — 0 15 b — 0 16 a — 0 17 a — 0 18 b — 0 19 a —0 20 b a −18 21 a — 0 22 b — 0 23 b — 0 24 c — 0 25 a — 0 26 b — 0 27 c— 0 28 b — 0 29 a — 0 30 a — 0 31 a — 0 32 b — 0 33 a a −22 34 a a −1835 a — 0 36 c — 0 37 a — 0 38 c — 0 39 a — 0 40 b — 0 41 a — 0 42 a — 043 a — 0 44 a — 0 45 a — 0 46 b — 0 47 a — 0 48 a — 0 49 a — 0 50 b — −151 a — 0 52 b — 0 53 b — 3 54 b — 0 55 b — 0 56 a — 0 57 a — 0 58 c — 059 a — 0 60 b — 0 61 b — 0 62 b — 0 63 b — 0 64 a — 0 65 a — 0 66 b — 067 a — 0 68 b — 0 69 a — 0 70 b — 0 71 b — 0 72 b — 2 73 b — −3 74 b — 175 a — 1 76 b — 4 77 a — 4 78 a — 2 79 a — 11 80 b b −35 81 a — −9 82 aa −17 83 a — −1 84 a — −8 85 a — −2 86 a — −11 87 c — 0 88 b — −2 89 a a−25 90 b c −41 91 b b −29 92 b a −31 93 b — 0 94 c — −13 95 a — 0 96 a —0 97 a — 1 98 b — −8 99 a — 4 100  a — −22 101  a — −25 102  a — −15103  a — −20 104  a — −15 105  b — −24 106  b — 0 107  b — −17 108  b —−19 109  a — −23 110  b — −23 111  b — −25 112  a — −9 113  b — 0 114  b— 0 115  b — 0 116  b — 0 117  b — 0 118  b — 0 119  b — 0 120  c — 0121  c — 0 122  b — 0 123  c — 0 124  b — 0 125  b — 0 126  c — 0 127  b— 0 128  c — 0 129  c — 0 130  c — 0 131  a — 0 132  b — 0 133  b — 0134  b — 0 135  c — 0 136  b — 0 137  b — 0 138  b — 0 139  b — 0 140  b— 0 141  b — 0 142  a — 0 143  a — 0 144  b — 0 145  a — 0 146  b — 0147  c — 0 148  b — −12 149  b — 0 150  b — 0 In the table are listedthe IC₅₀ values of the hMC-4R binding assay and the EC₅₀ values of thefunctional assay. The IC₅₀ and EC₅₀ values were grouped in 3 classes: a≦ 0.1 μM; b > 0.1 μM and ≦ 1.0 μM; c > 1.0 μM

C. In Vivo Food Intake Models 1. Spontaneous Feeding Paradigm

Food intake in rats is measured after i.p. or p.o. administration of thetest compound (see e.g. Chen, A. S. et al. Transgenic Res 2000 April;9(2):145-54).

2. Models of LPS-Induced Anorexia and Tumor-Induced Cachexia

Prevention or amelioration of anorexia induced by lipopolysaccharide(LPS) administration or cachexia induced by tumor growth is determinedupon i.p. or p.o. administration of test compounds to rats (see e.g.Marks, D. L.; Ling, N. and Cone, R. D. Cancer Res 2001 Feb. 15;61(4):1432-8).

D. In Vitro ADME Assays 1. Microsomal Stability Experimental Procedure

Pooled human liver microsomes (pooled male and female) and pooled ratliver microsomes (male Sprague Dawley rats) are prepared. Microsomes arestored at −80° C. prior to use.

Microsomes (final concentration 0.5 mg/ml), 0.1 M phosphate buffer pH7.4and test compound (final substrate concentration=3 μM; final DMSOconcentration=0.25%) are pre-incubated at 37° C. prior to the additionof NADPH (final concentration=1 mM) to initiate the reaction. The finalincubation volume is 25 μl. A control incubation is included for eachcompound tested where 0.1 M phosphate buffer pH7.4 is added instead ofNADPH (minus NADPH). Two control compounds are included with eachspecies. All incubations are performed singularly for each testcompound.

Each compound is incubated for 0, 5, 15, 30 and 45 min. The control(minus NADPH) is incubated for 45 min only. The reactions are stopped bythe addition of 50 μl methanol containing internal standard at theappropriate time points. The incubation plates are centrifuged at 2,500rpm for 20 min at 4° C. to precipitate the protein.

Quantitative Analysis

Following protein precipitation, the sample supernatants are combined incassettes of up to 4 compounds and analysed using generic LC-MS/MSconditions.

Data Analysis

From a plot of the peak area ratio (compound peak area/internal standardpeak area) against time, the gradient of the line is determined.Subsequently, half-life and intrinsic clearance are calculated using theequations below:

Elimination  rate  constant  (k) = (−gradient)${{Half}\mspace{14mu} {life}\mspace{14mu} \left( t_{1/2} \right)\left( \min \right)} = \frac{0.693}{k}$${{Intrinsic}\mspace{14mu} {Clearance}\mspace{14mu} \left( {CL}_{int} \right)\left( {{µl}\text{/}\min \text{/}{mg}\mspace{14mu} {protein}} \right)} = \frac{V \times 0.693}{t_{1/2}}$where  V = Incubation  volume  µl/mg  microsomal  protein.

Two control compounds are included in the assay and if the values forthese compounds are not within the specified limits the results arerejected and the experiment repeated.

2. Hepatocyte Stability Experimental Procedure

Suspensions of cryopreserved hepatocytes are used for human hepatocytestability assay (pooled from 3 individuals). All cryopreservedhepatocytes are purchased from in Vitro Technologies, Xenotech or TCS.

Incubations are performed at a test or control compound concentration of3 μM at a cell density of 0.5×10⁶ viable cells/mL. The final DMSOconcentration in the incubation is 0.25%. Control incubations are alsoperformed in the absence of cells to reveal any non-enzymaticdegradation.

Duplicate samples (50 μl) are removed from the incubation mixture at 0,5, 10, 20, 40 and 60 min (control sample at 60 min only) and added tomethanol, containing internal standard (100 μl), to stop the reaction.

Tolbutamide, 7-hydroxycoumarin, and testosterone are used as controlcompounds. The samples are centrifuged (2500 rpm at 4° C. for 20 min)and the supernatants at each time point are pooled for cassette analysisby LC-MS/MS using generic methods.

Data Analysis

From a plot of in peak area ratio (compound peak area/internal standardpeak area) against time, the gradient of the line is determined.Subsequently, half-life and intrinsic clearance are calculated using theequations below:

Elimination  rate  constant  (k) = (−gradient)${{Half}\mspace{14mu} {life}\mspace{14mu} \left( t_{1/2} \right)\left( \min \right)} = \frac{0.693}{k}$${{Intrinsic}\mspace{14mu} {Clearance}\mspace{14mu} \left( {CL}_{int} \right)\left( {{µl}\text{/}\min \text{/}{million}\mspace{14mu} {cells}} \right)} = \frac{V \times 0.693}{t_{1/2}}$where  V = Incubation  volume  (µl)/number  of  cells

3. Caco-2 Permeability (Bi-directional) Experimental Procedure

Caco-2 cells obtained from the ATCC at passage number 27 are used. Cells(passage number 40-60) are seeded on to Millipore Multiscreen Caco-2plates at 1×10⁵ cells/cm². They are cultured for 20 days in DMEM andmedia is changed every two or three days. On day 20 the permeabilitystudy is performed.

Hanks Balanced Salt Solution (HBSS) pH7.4 buffer with 25 mM HEPES and 10mM glucose at 37° C. is used as the medium in permeability studies.Incubations are carried out in an atmosphere of 5% CO₂ with a relativehumidity of 95%.

On day 20, the monolayers are prepared by rinsing both basolateral andapical surfaces twice with HBSS at 37° C. Cells are then incubated withHBSS in both apical and basolateral compartments for 40 min to stabilizephysiological parameters. HBSS is then removed from the apicalcompartment and replaced with test compound dosing solutions. Thesolutions are made by diluting 10 mM test compound in DMSO with HBSS togive a final test compound concentration of 10 μM (final DMSOconcentration 1%). The fluorescent integrity marker lucifer yellow isalso included in the dosing solution. Analytical standards are made fromdosing solutions. Test compound permeability is assessed in duplicate.On each plate compounds of known permeability characteristics are run ascontrols.

The apical compartment inserts are then placed into ‘companion’ platescontaining fresh HBSS. For basolateral to apical (B-A) permeabilitydetermination the experiment is initiated by replacing buffer in theinserts then placing them in companion plates containing dosingsolutions. At 120 min the companion plate is removed and apical andbasolateral samples diluted for analysis by LC-MS/MS. The startingconcentration (C_(o)) and experimental recovery is calculated from bothapical and basolateral compartment concentrations.

The integrity of the monolayers throughout the experiment is checked bymonitoring lucifer yellow permeation using fluorimetric analysis.Lucifer yellow permeation is low if monolayers have not been damaged.Test and control compounds are quantified by LC-MS/MS cassette analysisusing a 5-point calibration with appropriate dilution of the samples.Generic analytical conditions are used.

If a lucifer yellow P_(app) value is above QC limits in one individualtest compound well, then an n=1 result is reported. If lucifer yellowP_(app) values are above QC limits in both replicate wells for a testcompound, the compound is re-tested. Consistently high lucifer yellowpermeation for a particular compound in both wells indicates toxicity.No further experiments are performed in this case.

Data Analysis

The permeability coefficient for each compound (P_(app)) is calculatedfrom the following equation:

$P_{app} = \frac{{Q}/{t}}{C_{0} \times A}$

Where dQ/dt is the rate of permeation of the drug across the cells, C₀is the donor compartment concentration at time zero and A is the area ofthe cell monolayer. C₀ is obtained from analysis of donor and receivercompartments at the end of the incubation period. It is assumed that allof the test compound measured after 120 min incubation was initiallypresent in the donor compartment at 0 min. An asymmetry index (Al) isderived as follows:

${A\; I} = \frac{P_{app}\left( {B - A} \right)}{P_{app}\left( {A - B} \right)}$

An asymmetry index above unity shows efflux from the Caco-2 cells, whichindicates that the compound may have potential absorption problems invivo.

The apparent permeability (P_(app) (A-B)) values of test compounds arecompared to those of control compounds, atenolol and propranolol, thathave human absorption of approximately 50 and 90% respectively (Zhao, Y.H., et al., (2001). Evaluation of Human Intestinal Absorption Data andSubsequent Derivation of a Quantitative Structure-Activity Relationship(QSAR) with the Abraham Descriptors. Journal of Pharmaceutical Sciences.90 (6), 749-784). Talinolol (a known P-gp substrate (Deferme, S., Mols,R., Van Driessche, W., Augustijns, P. (2002). Apricot Extract Inhibitsthe P-gp-Mediated Efflux of Talinolol. Journal of PharmaceuticalSciences. 91(12), 2539-48)) is also included as a control compound toassess whether functional P-gp is present in the Caco-2 cell monolayer.

4. Cytochrome P450 Inhibition (5 Isoform IC₅₀ Determination))Experimental Procedure CYP1A Inhibition

Six test compound concentrations (0.05, 0.25, 0.5, 2.5, 5, 25 μM inDMSO; final DMSO concentration=0.35%) are incubated with human livermicrosomes (0.25 mg/ml) and NADPH (1 mM) in the presence of the probesubstrate ethoxyresorufin (0.5 μM) for 5 min at 37° C. The selectiveCYP1A inhibitor, alpha-naphthoflavone, is screened alongside the testcompounds as a positive control.

CYP2C9 Inhibition

Six test compound concentrations (0.05, 0.25, 0.5, 2.5, 5, 25 μM inDMSO; final DMSO concentration=0.25%) are incubated with human livermicrosomes (1 mg/ml) and NADPH (1 mM) in the presence of the probesubstrate tolbutamide (120 μM) for 60 min at 37° C. The selective CYP2C9inhibitor, sulphaphenazole, is screened alongside the test compounds asa positive control.

CYP2C19 Inhibition

Six test compound concentrations (0.05, 0.25, 0.5, 2.5, 5, 25 μM inDMSO; final DMSO concentration=0.25%) are incubated with human livermicrosomes (0.5 mg/ml) and NADPH (1 mM) in the presence of the probesubstrate mephenyloin (25 μM) for 60 min at 37° C. The selective CYP2C19inhibitor, tranylcypromine, is screened alongside the test compounds asa positive control.

CYP2D6 Inhibition

Six test compound concentrations (0.05, 0.25, 0.5, 2.5, 5, 25 μM inDMSO; final DMSO concentration=0.25%) are incubated with human livermicrosomes (0.5 mg/ml) and NADPH (1 mM) in the presence of the probesubstrate dextromethorphane (5 μM) for 30 min at 37° C. The selectiveCYP2D6 inhibitor, quinidine, is screened alongside the test compounds asa positive control.

CYP3A4 Inhibition

Six test compound concentrations (0.05, 0.25, 0.5, 2.5, 5, 25 μM inDMSO; final DMSO concentration 0.26%) are incubated with human livermicrosomes (0.25 mg/ml) and NADPH (1 mM) in the presence of the probesubstrate midazolam (2.5 μM) for 5 min at 37° C. The selective CYP3A4inhibitor, ketoconazole, is screened alongside the test compounds as apositive control.

For the CYP1A incubations, the reactions are terminated by the additionof methanol, and the formation of the metabolite, resorufin, ismonitored by fluorescence (excitation wavelength=535 nm, emissionwavelength=595 nm). For the CYP2C9, CYP2C19, CYP2D6, and CYP3A4incubations, the reactions are terminated by the addition of methanolcontaining internal standard. The samples are then centrifuged, and thesupernatants are combined, for the simultaneous analysis of4-hydroxytolbutamide, 4-hydroxymephenyloin, dextrorphan, and1-hydroxymidazolam plus internal standard by LC-MS/MS. Generic LC-MS/MSconditions are used. Formic acid in deionised water (finalconcentration=0.1%) is added to the final sample prior to analysis. Adecrease in the formation of the metabolites compared to vehicle controlis used to calculate an IC₅₀ value (test compound concentration whichproduces 50% inhibition).

5. Plasma Protein Binding (10%) Experimental Procedure

Solutions of test compound (5 μM, 0.5% final DMSO concentration) areprepared in buffer (pH 7.4) and 10% plasma (v/v in buffer). Theexperiment is performed using equilibrium dialysis with the twocompartments separated by a semi-permeable membrane. The buffer solutionis added to one side of the membrane and the plasma solution to theother side. Standards are prepared in plasma and buffer and areincubated at 37° C. Corresponding solutions for each compound areanalyzed in cassettes by LC-MS/MS.

Quantitative Analysis

After equilibration, samples are taken from both sides of the membrane.The solutions for each batch of compounds are combined into two groups(plasma-free and plasma-containing) then cassette analyzed by LC-MS/MSusing two sets of calibration standards for plasma-free (7 points) andplasma-containing solutions (6 points). Generic LC-MS/MS conditions areused. Samples are quantified using standard curves prepared in theequivalent matrix. The compounds are tested in duplicate.

A control compound is included in each experiment.

Data Analysis

${f\; u} = \frac{1 - \left( \left( {{P\; C} - {P\; F}} \right) \right)}{\left( {P\; C} \right)}$

fu=fraction unboundPC=sample concentration in protein containing sidePF=sample concentration in protein free sidefu at 10% plasma is converted to fu 100% plasma using the followingequation:

${f\; u_{100\%}} = \frac{f\; u_{10\%}}{10 - \left( {9*f\; u_{10\%}} \right)}$

Examples of a Pharmaceutical Composition

As a specific embodiment of an oral composition of a compound of thepresent invention, 33 mg of Example 9 is formulated with sufficientfinely divided lactose to provide a total amount of 580 to 590 mg tofill a size 0 hard gelatin capsule.

As another specific embodiment of an oral composition of a compound ofthe present invention, 37 mg of Example 17 is formulated with sufficientfinely divided lactose to provide a total amount of 580 to 590 mg tofill a size 0 hard gelatin capsule.

While the invention has been described and illustrated in reference tocertain preferred embodiments thereof, those skilled in the art willappreciate that various changes, modifications and substitutions can bemade therein without departing from the spirit and scope of theinvention. For example, effective dosages, other than the preferreddoses as set forth above, may be applicable as a consequence of thespecific pharmacological responses observed and may vary depending uponthe particular active compound selected, as well as from the type offormulation and mode of administration employed, and such expectedvariations or differences in the results are contemplated in accordancewith the objects and practices of the present invention. It is intended,therefore, that the invention be limited only by the scope of the claimswhich follow and that such claims be interpreted as broadly as isreasonable.

1. A compound according to formula (I)

and enantiomers, diastereomers, tautomers, solvates and pharmaceuticallyacceptable salts thereof, wherein A is —NH—, —CH₂—, —CH₂—CH₂— or a bond;X is H, phenyl, phenyl which is fused with a saturated heterocyclic 5-or 6-membered ring, wherein the heterocyclic ring may contain 1 or 2heteroatoms selected from O and N and wherein the heterocyclic ring mayfurther be optionally substituted by an oxo group, 4 to 8-memberedsaturated or unsaturated heterocyclyl containing 1 or 2 heteroatomsselected from N, O and S, 5- to 6-membered heteroaryl containing 1 or 2heteroatoms selected from N, O and S, or —C(O)—R⁶, wherein each phenyl,heterocyclyl and heteroaryl is optionally substituted by 1 to 3 R¹⁴and/or 1R^(4b) and/or 1 R⁵; R¹ and R² are independently from each otherselected from H, C₁₋₆ alkyl, C₁₋₆ alkylene-O—C₁₋₆ alkyl, C₁₋₃alkylene-heterocyclyl, and C₁₋₆ alkylene-C₃₋₇, cycloalkyl, wherein eachalkyl, alkylene, heterocyclyl and cycloalkyl is optionally substitutedby OH, or R¹ and R² form together with the nitrogen atom to which theyare attached a 5 to 6-membered ring which may additionally contain 1oxygen atom in the ring and which ring is optionally substituted by oneor more substituents selected from OH, C₁₋₆ alkyl, O—C₁₋₆ alkyl, C₀₋₃alkylene-C₃₋₅ cycloalkyl, C₁₋₆ alkylene-O—C₁₋₆ alkyl or (CH₂)₀₋₃-phenyl;R^(4a) is halogen, CN, C₁₋₆ alkyl, optionally substituted with one ormore halogen atoms, O—C₁₋₆ alkyl, optionally substituted with one ormore halogen atoms, or OH; R^(4b) is C(O)NH₂, C(O)OH C(O)NH—C₁₋₆ alkyl,C(O)N—(C₁₋₆ alkyl)₂, SO₂—C₁₋₆ alkyl, C(O)NH—SO₂—C₁₋₆ alkyl, oxo, wherebythe ring is at least partially saturated, NH₂, NH—C₁₋₆ alkyl, N—(C₁₋₆alkyl)₂, NH—SO₂—CH₃, or NH—SO₂—CF₃; R⁵ is 5 to 6-membered saturated orunsaturated heterocyclyl containing 1 to 3 heteroatoms selected from N,O and S, or 5 to 6-membered heteroaryl containing 1 to 3 heteroatomsselected from N, O and S, wherein the heterocyclyl and the heteroarylare optionally substituted by 1 or 2 R¹⁴; R⁶ is H, C₁₋₆alkyl, optionallysubstituted with one or more halogen atoms, phenyl or 4 to 8-memberedsaturated or unsaturated heterocyclyl containing 1 to 3 heteroatomsselected from N, O and S, wherein each phenyl and heterocyclyl isoptionally substituted by 1 to 3 R¹⁴ and/or 1R⁵; R³ is —(CR⁸R⁹)_(n)-T;R⁸ and R⁹ are independently from each other selected from H, OH,halogen, C₁₋₆ alkyl, and O—C₁₋₆ alkyl; n is 1, 2, 3, 4, 5 or 6; T is

or NR¹²R¹³; R¹⁰ is H, NH₂, OH, C₁₋₆ alkyl, optionally substituted by oneor more substituents selected from halogen, OH, and O—C₁₋₆alkyl, R¹⁴ isO—C₁₋₆ alkyl, wherein alkyl is optionally substituted by one or moresubstituents selected from halogen, OH, and O—C₁₋₆ alkyl, halogen,NH(C₁₋₆ alkyl), N(C₁₋₆ alkyl)₂, phenyl or heteroaryl, wherein phenyl andheteroaryl are optionally substituted by 1 to 3 R^(4a); q is 1 or 2; Yis CH₂, NR¹¹ or O; R¹¹ is H, C₁₋₆alkyl or (CH₂)₀₋₆—C₃₋₇cycloalkyl; R¹²and R¹³ are independently from each other selected from H, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkinyl, (CH₂)₀₋₂—C₃₋₇cycloalkyl andC₁₋₆alkylene-O—C₁₋₆ alkyl, wherein C₁₋₆ alkyl, C₁₋₆ alkylene and C₃₋₇cycloalkyl are optionally substituted by 1 to 3 R¹⁴; R¹⁴ is halogen, CN,C₁₋₆ alkyl, optionally substituted with one or more substituentsselected from halogen, OH, O—C₁₋₆ alkyl, O—C₃₋₇ cycloalkyl, O—C(O)C₁₋₆alkyl, O—C(O)C₃₋₇ cycloalkyl, O—C₁₋₆ alkyl, optionally substituted withone or more substituents selected from halogen, OH, O—C₁₋₆ alkyl, O—C₃₋₇cycloalkyl, O—C(O)C₁₋₆ alkyl, O—C(O)C₃₋₇cycloalkyl, or OH.
 2. Thecompound according to claim 1, wherein A is —NH—, —CH₂—, —CH₂—CH₂— or abond; X is H, phenyl, phenyl which is fused with a saturatedheterocyclic 6-membered ring, wherein the heterocyclic ring may contain1 or 2 heteroatoms selected from O and N and wherein the heterocyclicring may further be optionally substituted by an oxo group, 4 to8-membered saturated or unsaturated heterocyclyl containing 1 or 2heteroatoms selected from N, O and S, 5- to 6-membered heteroarylcontaining 1 or 2 heteroatoms selected from N, O and S, or —C(O)—R⁶,wherein each phenyl, heterocyclyl and heteroaryl is optionallysubstituted by 1 to 3 R¹⁴ and/or 1R^(4b) and/or 1R⁵; R¹ and R² areindependently from each other selected from H, C₁₋₆ alkyl, C₁₋₆alkylene-O—C₁₋₆ alkyl, C₁₋₃ alkylene-heterocyclyl, and C₁₋₆alkylene-C₃₋₇ cycloalkyl, or R¹ and R² form together with the nitrogenatom to which they are attached a 5 to 6-membered ring which mayadditionally contain 1 oxygen atom in the ring and which ring isoptionally substituted by one or more substituents selected from OH,C₁₋₆ alkyl, O—C₁₋₆ alkyl, C₀₋₃ alkylene-C₃₋₅ cycloalkyl, C₁₋₆alkylene-O—C₁₋₆ alkyl or (CH₂)₀₋₃-phenyl; R^(4a) and R¹⁴ areindependently from each other selected from halogen, CN, C₁₋₆ alkyl,optionally substituted with one or more halogen atoms, O—C₁₋₆ alkyl,optionally substituted with one or more halogen atoms, or OH; R^(ob) isC(O)NH₂, C(O)NH—C₁₋₆ alkyl, C(O)N—(C₁₋₆ alkyl)₂, SO₂—C₁₋₆ alkyl,C(O)NH—SO₂—C₁₋₆ alkyl, NH₂, NH—C₁₋₆ alkyl, N—(C₁₋₆ alkyl)₂, NH—SO₂—CH₃,or NH—SO₂—CF₃; R⁵ is 5 to 6-membered saturated or unsaturatedheterocyclyl containing 1 to 3 heteroatoms selected from N, O and S or 5to 6-membered heteroaryl containing 1 to 3 heteroatoms selected from N,O and S, wherein the heterocyclyl and the heteroaryl are optionallysubstituted by 1 or 2 R¹⁴; R⁶ is H, C₁₋₆ alkyl, optionally substitutedwith one or more halogen atoms, phenyl or 4 to 8-membered saturated orunsaturated heterocyclyl containing 1 to 3 heteroatoms selected from N,O and S, wherein each phenyl and heterocyclyl is optionally substitutedby 1 to 3 R¹⁴ and/or 1R⁵; R³ is —(CR⁸R⁹)_(n)-T; R⁸ and R⁹ areindependently from each other selected from H, OH, halogen, C₁₋₆ alkyl,and O—C₁₋₆ alkyl; n is 1, 2, 3, 4, 5 or 6; T is

or NR¹²R¹³; R¹⁰ is H, NH₂, C₁₋₆ alkyl, halogen, NH(C₁₋₆ alkyl), N(C₁₋₆alkyl)₂, phenyl or heteroaryl, wherein phenyl and heteroaryl areoptionally substituted by 1 to 3 R^(4a); Y is CH₂, NR¹¹ or O; R¹¹ is H,C₁₋₆ alkyl or (CH₂)₀₋₆—C₃₋₇ cycloalkyl; R¹² and R¹³ are independentlyfrom each other selected from H, C₁₋₆ alkyl, (CH₂)₀₋₂—C₃₋₇ cycloalkyland C₁₋₆ alkylene-O—C₁₋₆ alkyl; wherein C₁₋₆ alkyl, C₁₋₆ alkylene andC₃₋₇ cycloalkyl are optionally substituted by 1 to 3 R¹⁴.
 3. Thecompound of claim 1, wherein A is NH— or a bond.
 4. The compound ofclaim 1, wherein R¹ and R² are independently from each other C₃₋₆ alkylor R¹ and R² form together with the nitrogen atom to which they areattached a 5 to 6-membered ring which may additionally contain 1 oxygenatom in the ring and which ring is optionally substituted by one or moresubstituents selected from OH, C₁₋₆ alkyl, C₀₋₃ alkylene-C_(m)cycloalkyl, O—C₁₋₆ alkyl, C₁₋₆ alkylene-O—C₁₋₆ alkyl or (CH₂)₀₋₃-phenyl.5. The compound of claim 1, wherein T is NR¹²R¹³.
 6. The compound ofclaim 5, wherein R¹² and R¹³ are independently from each other selectedfrom H, C₁₋₃ alkyl and (CH₂)₀₋₂—C₃₋₆ cycloalkyl, wherein alkyl andcycloalkyl are optionally substituted by 1 to 3 R¹⁴.
 7. The compound ofclaim 1, wherein T is selected from


8. The compound of claim 7, wherein Y is CH₂ or NR¹¹ and R¹⁰ is H, NH₂,C₁₋₆ alkyl, NH(C₁₋₆ alkyl) or N(C₁₋₆alkyl)₂.
 9. The compound of claim 1,wherein X is H, phenyl which is fused with a saturated heterocyclic6-membered ring, wherein the heterocyclic ring may contain 1 or 2heteroatoms selected from O and N and wherein the heterocyclic ring mayfurther be optionally substituted by an oxo group, or 4 to 8-memberedsaturated or unsaturated heterocyclyl containing 1 or 2 heteroatomsselected from N, O and S, wherein each phenyl or heterocyclyl isoptionally substituted by 1 to 3 R¹⁴ and/or 1R⁵.
 10. The compound ofclaim 1, wherein X is phenyl or 5 to 6-membered heteroaryl containing 1or 2 heteroatoms selected from N, O and S, wherein each phenyl andheteroaryl is optionally substituted by 1 to 3 R¹⁴ and/or 1R^(4b) and/or1R⁵.
 11. The compound of claim 10, wherein X is phenyl.
 12. The compoundof claim 10, wherein X is pyridyl.
 13. (canceled)
 14. The compound ofclaim 1, wherein said compound is a melanocortin-4 receptor antagonist.15. A method for the treatment or prophylaxis of a disorder, disease, orcondition responsive to the inactivation of the melanocortin-4 receptorin a mammal, wherein said method comprises administering a compositioncomprising the compound of claim 1 to said mammal.
 16. The method ofclaim 15, wherein said disorder, disease, or condition is cancercachexia, muscle wasting, anorexia, amytrophic lateral sclerosis (ALS),anxiety and/or depression.
 17. A pharmaceutical composition comprising athe compound of claim 1 and a pharmaceutically acceptable carrier.